Search results for: autosomal STR

Authors: Yessengali Ussenbekov, Valery Terletskiy, Orik Zhanserkenova, Shynar Kasymbekova, Indira Beyshova, Aitkali Imanbayev, Almas Serikov

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Currently, there are 46 hereditary diseases afflicting cattle with known molecular genetic diagnostic methods developed for them. Genetic anomalies frequently occur in the Holstein cattle breeds from American and Canadian bloodlines. The data on the incidence of BLAD, CVM, DUMPS and BC autosomal recessive lethal mutations in pedigree animals are discordant, the detrimental allele incidence rates are high for the Holstein cattle breed, whereas the incidence rates of these mutations are low in some breeds or they are completely absent. Data were obtained on the basis of frozen semen of stud bulls. DNA was extracted from the semen with the DNA-Sorb-B extraction kit. The lethal mutation in the genes CD18, SLC35A3, UMP and ASS of Alatau stud bulls (N=124) was detected by polymerase chain reaction and RFLP analysis. It was established that stud bulls of the local Alatau breed were not carriers of the BLAD, CVM, DUMPS, and BC detrimental mutations. However, with a view to preventing the dissemination of hereditary diseases it is recommended to monitor the pedigree stock using molecular genetic methods.

Keywords: PCR, autosomal recessive point mutation, BLAD, CVM, DUMPS, BC, stud bulls

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Authors: H. Imad, Q. Cheah, J. Mohammad, O. Aamera

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The aim of this study is twofold. One is to determine the genetic structure of Iraq population and the second objective of the study was to evaluate the importance of these loci for forensic genetic purposes. FTA® Technology (FTA™ paper DNA extraction) utilized to extract DNA. Twenty STR loci and Amelogenin including D3S1358, D13S317, PentaE, D16S539, D18S51, D2S1338, CSF1PO, Penta D, THO1, vWA, D21S11, D7S820, TPOX, D8S1179, FGA, D2S1338, D5S818, D6S1043, D12S391, D19S433, and Amelogenin amplified by using power plex21® kit. PCR products detected by genetic analyzer 3730xL then data analyzed by PowerStatsV1.2. Based on the allelic frequencies, several statistical parameters of genetic and forensic efficiency have been estimated. This includes the homozygosity and heterozygosity, effective number of alleles (n), the polymorphism information content (PIC), the power of discrimination (DP), and the power of exclusion (PE). The power of discrimination values for all tested loci was from 75% to 96% therefore, those loci can be safely used to establish a DNA-based database for Iraq population.

Keywords: autosomal STR, genetic variation, Middle and South of Iraq, statistical parameters

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Authors: Bajraktarevic Adnan, Djukic Branka, Sporisevic Lutvo, Krdzalic Zecevic Belma, Uzicanin Sajra, Hadzimuratovic Admir, Hadzimuratovic Hadzipasic Emina, Abduzaimovic Alisa, Kustric Amer, Suljevic Ismet, Serafi Ismail, Tahmiscija Indira, Khatib Hakam, Semic Jusufagic Aida, Haas Helmut, Vladicic Aleksandra, Aplenc Richard, Kadic Deovic Aida

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Introduction: Joubert syndrome has an autosomal recessive pattern of inheritance. It is referred as the brain malfunctioning and caused due to the underdevelopment of the cerebellar vermis. Associated conditions involving the eye, the kidney, and ocular disease are well described. Aims: Research helps us better understand this diseases, Joubert syndrome and can lead to advances in diagnosis and treatment. Methods: Different several conditions have been described in which the molar tooth sign and characteristics of Joubert syndrome in ten different places in the world. Carrier testing and diagnosis are available if one of these gene mutations has been identified in an affected family member. Results: Authors have described eleven cases during twenty years of Joubert syndrome. It is a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic molar tooth sign, and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. We made confirmation of diagnosis in twin sisters with Joubert syndrome with renal anomalies. Ocular symptoms have existed in seven cases (63.64%) from total eleven. Eleven cases were different sex, five boys (45.45%) and six girls (54.44%). Conclusions: Joubert syndrome is inherited as an autosomal recessive genetic disorder with several features of the disease.

Keywords: Joubert syndrome, cerebellooculorenal syndrome, autosomal recessive genetic disorder (ARGD), children

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Authors: Dana Gabriková, Martin Mistrík, Jarmila Bernasovská, Iveta Tóthová, Jana Kisková

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The Roma (Gypsies) is a transnational minority with a high degree of consanguineous marriages. Similar to other genetically isolated founder populations, the Roma harbor a number of unique or rare genetic disorders. This paper discusses about a rare form of Charcot-Marie-Tooth disease – type 4G (CMT4G), also called Hereditary Motor and Sensory Neuropathy type Russe, an autosomal recessive disease caused by mutation private to Roma characterized by abnormally increased density of non-myelinated axons. CMT4G was originally found in Bulgarian Roma and in 2009 two putative causative mutations in the HK1 gene were identified. Since then, several cases were reported in Roma families mainly from Bulgaria and Spain. Here we present a Slovak Roma family in which CMT4G was diagnosed on the basis of clinical examination and genetic testing. This case is a further proof of the role of the HK1 gene in pathogenesis of the disease. It confirms that mutation in the HK1 gene is a common cause of autosomal recessive CMT disease in Roma and should be considered as a common part of a diagnostic procedure.

Keywords: gypsies, HK1, HSMN-Russe, rare disease

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Authors: Fouad Chebib, Marie Hogan, Ziad El-Zoghby, Maria Irazabal, Sarah Senum, Christina Heyer, Charles Madsen, Emilie Cornec-Le Gall, Atta Behfar, Barbara Ehrlich, Peter Harris, Vicente Torres

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Background: Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2) cause autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a systemic disease associated with several extrarenal manifestations. Animal models have suggested an important role for the polycystins in cardiovascular function. The aim of the current study is to evaluate the association of various cardiomyopathies in a large cohort of patients with ADPKD. Methods: Clinical data was retrieved from medical records for all patients with ADPKD and cardiomyopathies (n=159). Genetic analysis was performed on available DNA by direct sequencing. Results: Among the 58 patients included in this case series, 39 patients had idiopathic dilated cardiomyopathy (IDCM), 17 had hypertrophic obstructive cardiomyopathy (HOCM), and 2 had left ventricular noncompaction (LVNC). The mean age at cardiomyopathy diagnosis was 53.3, 59.9 and 53.5 years in IDCM, HOCM and LVNC patients respectively. The median left ventricular ejection fraction at initial diagnosis of IDCM was 25%. Average basal septal thickness was 19.9 mm in patients with HOCM. Genetic data was available in 19, 8 and 2 cases of IDCM, HOCM, and LVNC respectively. PKD1 mutations were detected in 47.4%, 62.5% and 100% of IDCM, HOCM and LVNC cases. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (~15%). The prevalence of IDCM, HOCM, and LVNC in our ADPKD clinical cohort was 1:17, 1:39 and 1:333 respectively. When compared to the general population, IDCM and HOCM was approximately 10-fold more prevalent in patients with ADPKD. Conclusions: In summary, we suggest that PKD1 or PKD2 mutations may predispose to idiopathic dilated or hypertrophic cardiomyopathy. There is a trend for patients with PKD2 mutations to develop the former and for patients with PKD1 mutations to develop the latter. Predisposition to various cardiomyopathies may be another extrarenal manifestation of ADPKD.

Keywords: autosomal dominant polycystic kidney (ADPKD), polycystic kidney disease, cardiovascular, cardiomyopathy, idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, left ventricular noncompaction

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Authors: Vidhi Chandra, Arshpreet Singh Grewal

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A five-year-old male child born from non-consanguineous marriage, who presented with complaints of growth retardation and no appreciable increase in the penile size since birth and he was posted for de-gloving of penis with dissection of corpora under anaesthesia. After thorough preoperative evaluation it was revealed that patient had peculiar facial dysmorphism that of Robinow Syndrome, high arched palate, Mallampati grade III, mesomelic limbs, scoliotic spine and short stature. All routine investigation were within normal limit, electrocardiography (ECG) and 2D-Echocardiography (ECHO) were normal. In antero-posterior roentgenogram chest showed butterfly and hemivertebrae at multiple levels. The patient was considered to be ASA II. On the day of surgery after ensuring fasting of 6 hours, patient was taken in operation theatre, all standard ASA monitoring was done with ECG, non-invasive blood pressure, peripheral oxygen saturation (SpO2) and body temperature. The patient was pre-oxygenated with 100% oxygen with anatomical face mask. General anaesthesia was induced with Sevoflurane 1-8%, and airway was secured with an appropriate size supraglottic airway and anaesthesia was maintained with nitrous oxide and oxygen in 1:1 ratio along with sevoflurane 2%. An ultrasound guided caudal block was given owing to the skeletal deformities making it difficult even under USG guidance. Post operatively patient was given supportive care with proper hydration, antibiotics, anti-inflammatory and analgesics. He was discharged the next day and followed up weekly for a month. DISCUSSION Robinow syndrome is genetically inherited as autosomal dominant, autosomal recessive or heterogenous disorder involving tyrosine kinase ROR2 gene located on chromosome 9. It has low incidence with no preponderance for any gender. Though intelligence is normal but developmental delay and mental retardation occurs in 20%cases

Keywords: Robinow Syndrome, dwarfism, paediatric, anaesthesia

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Authors: Amirreza Razzaghipour Sorkhab

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One of the most common disorders among humans is hearing impairment. This paper provides an evidence base that recovers understanding of Meniere’s disease and highlights the physical and mental health correlates of the disorder. Meniere's disease is more common in the elderly. The term idiopathic endolymphatic hydrops has been attributed to this disease by some in the previous. Meniere’s disease demonstrations a genetic tendency, and a family history is found in 10% of cases, with an autosomal dominant inheritance pattern. The COCH gene may be one of the hereditary factors contributing to Meniere’s disease, and the possibility of a COCH mutation should be considered in patients with Meniere’s disease symptoms. Should be considered Missense mutations in the COCH gene cause the autosomal dominant sensorineural hearing loss and vestibular disorder. Meniere’s disease is a complex, heterogeneous disorder of the inner ear and that is characterized by episodes of vertigo lasting from minutes to hours, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. The existing evidence supports the suggestion that age and sleep disorder are risk factors for Meniere's disease. Many factors have been reported to precipitate the progress of Menier, including endolymphatic hydrops, immunology, viral infection, inheritance, vestibular migraine, and altered intra-labyrinthine fluid dynamics. Although there is currently no treatment that has a proven helpful effect on hearing levels or on the long-term evolution of the disease, however, in the primary stages, the hearing may improve among attacks, but a permanent hearing loss occurs in the majority of cases. Current publications have proposed a role for the intratympanic use of medicine, mostly aminoglycosides, for the control of vertigo. more than 85% of patients with Meniere's disease are helped by either changes in lifestyle and medical treatment or minimally aggressive surgical procedures such as intratympanic steroid therapy, intratympanic gentamicin therapy, and endolymphatic sac surgery. However, unilateral vestibular extirpation methods (intratympanic gentamicin, vestibular nerve section, or labyrinthectomy) are more predictable but invasive approaches to control the vertigo attacks. Medical therapy aimed at reducing endolymph volume, such as low-sodium diet, diuretic use, is the typical initial treatment.

Keywords: meniere's disease, endolymphatic hydrops, hearing loss, vertigo, tinnitus, COCH gene

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Authors: Angelis P. Barlampas

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Objective: The confusion of terms is a common practice in many situations of the everyday life. But, in some circumstances, such as in medicine, the precise meaning of a word curries a critical role for the health of the patient. Fahr disease and Fahr syndrome are often falsely used interchangeably, but they are two different conditions with different physical histories of different etiology and different medical management. A case of the seldom Fahr disease is presented, and a comparison with the more common Fahr syndrome follows. Materials and method: A 72 years old patient came to the emergency department, complaining of some kind of non specific medal disturbances, like anxiety, difficulty of concentrating, and tremor. The problems had a long course, but he had the impression of getting worse lately, so he decided to check them. Past history and laboratory tests were unremarkable. Then, a computed tomography examination was ordered. Results: The CT exam showed bilateral, hyperattenuating areas of heavy, dense calcium type deposits in basal ganglia, striatum, pallidum, thalami, the dentate nucleus, and the cerebral white matter of frontal, parietal and iniac lobes, as well as small areas of the pons. Taking into account the absence of any known preexisting illness and the fact that the emergency laboratory tests were without findings, a hypothesis of the rare Fahr disease was supposed. The suspicion was confirmed with further, more specific tests, which showed the lack of any other conditions which could probably share the same radiological image. Differentiating between Fahr disease and Fahr syndrome. Fahr disease: Primarily autosomal dominant Symmetrical and bilateral intracranial calcifications The patient is healthy until the middle age Absence of biochemical abnormalities. Family history consistent with autosomal dominant Fahr syndrome :Earlier between 30 to 40 years old. Symmetrical and bilateral intracranial calcifications Endocrinopathies: Idiopathic hypoparathyroidism, secondary hypoparathyroidism, hyperparathyroidism, pseudohypoparathyroidism ,pseudopseudohypoparathyroidism, e.t.c The disease appears at any age There are abnormal laboratory or imaging findings. Conclusion: Fahr disease and Fahr syndrome are not the same illness, although this is not well known to the inexperienced doctors. As clinical radiologists, we have to inform our colleagues that a radiological image, along with the patient's history, probably implies a rare condition and not something more usual and prompt the investigation to the right route. In our case, a genetic test could be done earlier and reveal the problem, and thus avoiding unnecessary and specific tests which cost in time and are uncomfortable to the patient.

Keywords: fahr disease, fahr syndrome, CT, brain calcifications

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Authors: Aran Abd Al Rahman

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Joubert syndrome regards as a congenital cerebellar ataxia caused by autosomal recessive carried on X chromosome. The disease diagnosed by brain imaging—the so-called molar tooth sign. Neurological signs were present from the neonatal period and include hypotonia progressing to ataxia, global developmental delay, ocular motor apraxia, and breathing dysregulation. These signs are variably associated with multiorgan involvement, mainly of the retina, kidneys, skeleton, and liver. 30 causative genes have been identified so far, all of which encode for proteins of the primary cilium or its apparatus, The purpose of our project was to detect the mutant gene (INPP5E gene) which cause Joubert syndrome. There were many methods used for diagnosis such as MRI and CT- scan and molecular diagnosis by doing ARMS PCR for detection of mutant gene that we were used in this research project. In this research for individual family which reported, the two children with parents, the two children were affected and were carrier.

Keywords: Joubert syndrome, genetic disease, Kurdistan region, Sulaimani

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Authors: Hamid Mustafa, Huson J. Heather, Kim Eiusoo, Adeela Ajmal, Tad S. Sonstegard

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The objective of this study was to evaluate the informativeness of Bovine high density SNPs genotyping in Sahiwal cattle population. This is a first attempt to assess the Bovine HD SNP genotyping array in any Pakistani indigenous cattle population. To evaluate these SNPs on genome wide scale, we considered 777,962 SNPs spanning the whole autosomal and X chromosomes in Sahiwal cattle population. Fifteen (15) non related gDNA samples were genotyped with the bovine HD infinium. Approximately 500,939 SNPs were found polymorphic (MAF > 0.05) in Sahiwal cattle population. The results of this study indicate potential application of Bovine High Density SNP genotyping in Pakistani indigenous cattle population. The information generated from this array can be applied in genetic prediction, characterization and genome wide association studies of Pakistani Sahiwal cattle population.

Keywords: Sahiwal cattle, polymorphic SNPs, genotyping, Pakistan

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Authors: Reham Khalaf-Nazzal, Imad Dweikat, Paula Gimenez, Iker Oyenarte, Alfonso Martinez-Cruz, Domonik Muller

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Metal cation transport mediator (CNNM) gene family comprises 4 isoforms that are expressed in various human tissues. Structurally, CNNMs are complex proteins that contain an extracellular N-terminal domain preceding a DUF21 transmembrane domain, a ‘Bateman module’ and a C-terminal cNMP-binding domain. Mutations in CNNM2 cause familial dominant hypomagnesaemia. Growing evidence highlights the role of CNNM2 in neurodevelopment. Mutations in CNNM2 have been implicated in epilepsy, intellectual disability, schizophrenia, and others. In the present study, we aim to elucidate the function of CNNM2 in the developing brain. Thus, we present the genetic origin of symptoms in two family cohorts. In the first family, three siblings of a consanguineous Palestinian family in which parents are first cousins, and consanguinity ran over several generations, presented a varying degree of intellectual disability, cone-rod dystrophy, and autism spectrum disorder. Exome sequencing and segregation analysis revealed the presence of homozygous pathogenic mutation in the CNNM2 gene, the parents were heterozygous for that gene mutation. Magnesium blood levels were normal in the three children and their parents in several measurements. They had no symptoms of hypomagnesemia. The CNNM2 mutation in this family was found to locate in the CBS1 domain of the CNNM2 protein. The crystal structure of the mutated CNNM2 protein was not significantly different from the wild-type protein, and the binding of AMP or MgATP was not dramatically affected. This suggests that the CBS1 domain could be involved in pure neurodevelopmental functions independent of its magnesium-handling role, and this mutation could have affected a protein partner binding or other functions in this protein. In the second family, another autosomal dominant CNNM2 mutation was found to run in a large family with multiple individuals over three generations. All affected family members had hypomagnesemia and hypermagnesuria. Oral supplementation of magnesium did not increase the levels of magnesium in serum significantly. Some affected members of this family have defects in fine motor skills such as dyslexia and dyslalia. The detected mutation is located in the N-terminal part, which contains a signal peptide thought to be involved in the sorting and routing of the protein. In this project, we describe heterogenous clinical phenotypes related to CNNM2 mutations and protein functions. In the first family, and up to the authors’ knowledge, we report for the first time the involvement of CNNM2 in retinal photoreceptor development and function. In addition, we report the presence of a neurophenotype independent of magnesium status related to the CNNM2 protein mutation. Taking into account the different modes of inheritance and the different positions of the mutations within CNNM2 and its different structural and functional domains, it is likely that CNNM2 might be involved in a wide spectrum of neuropsychiatric comorbidities with considerable varying phenotypes.

Keywords: magnesium transport, autosomal recessive, autism, neurodevelopment, CBS domain

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Authors: Kakali Roy, Sahana P. Raju, Subhra Dhar, Sandipan Dhar

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Introduction: Xeroderma pigmentosa (XP) is a rare inherited (autosomal recessive) disease resulting from impairment in DNA repair that involves recognition and repair of ultraviolet radiation (UVR) induced DNA damage in the nucleotide excision repair pathway. Which results in increased photosensitivity, UVR induced damage to skin and eye, increased susceptibility of skin and ocular cancer, and progressive neurodegeneration in some patients. XP is present worldwide, with higher incidence in areas having frequent consanguinity. Being extremely rare, there is limited literature on XP and associated complications. Here, the clinico-pathological experience (spectrum of clinical presentation, histopathological findings of malignant skin lesions, and progression) of managing 8 cases of XP is presented. Methodology: A retrospective study was conducted in a pediatric tertiary care hospital in eastern India during a ten-year period from 2013 to 2022. A clinical diagnosis was made based on severe sun burn or premature photo-aging and/or onset of cutaneous malignancies at early age (1st decade) in background of consanguinity and autosomal recessive inheritance pattern in family. Results: The mean age of presentation was 1.2 years (range of 7month-3years), while three children presented during their infancy. Male to female ratio was 5:3, and all were born of consanguineous marriage. They presented with dermatological manifestations (100%) followed by ophthalmic (75%) and/or neurological symptoms (25%). Patients had normal skin at birth but soon developed extreme sensitivity to UVR in the form of exaggerated sun tanning, burning, and blistering on minimal sun exposure, followed by abnormal skin pigmentation like freckles and lentiginosis. Subsequently, over time there was progressive xerosis, atrophy, wrinkling, and poikiloderma. Six patients had varied degree of ocular involvement, while three of them had severe manifestation, including madarosis, tylosis, ectropion, Lagopthalmos, Pthysis bulbi, clouding and scarring of the cornea with complete or partial loss of vision, and ophthalmic malignancies. 50% (n=4) cases had skin and ocular pre-malignant (actinic keratosis) and malignant lesions, including melanoma and non melanoma skin cancer (NMSC) like squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in their early childhood. One patient had simultaneous occurrence of multiple malignancies together (SCC, BCC, and melanoma). Subnormal intelligence was noticed as neurological feature, and none had sensory neural hearing loss, microcephaly, neuroregression, or neurdeficit. All the patients had been being managed by a multidisciplinary team of pediatricians, dermatologists, ophthalmologists, neurologists and psychiatrists. Conclusion: Although till date there is no complete cure for XP and the disease is ultimately fatal. But increased awareness, early diagnosis followed by persistent vigorous protection from UVR, and regular screening for early detection of malignancies along with psychological support can drastically improve patients’ quality of life and life expectancy. Further research is required on formulating optimal management of XP, specifically the role and possibilities of gene therapy in XP.

Keywords: childhood malignancies, dermato-pathological findings, eastern India, Xeroderma pigmentosa

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Authors: Gagandeep Singh Digra, Pawan Kumar, Mandeep Kaur Sidhu

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INTRODUCTION: Chronic Progressive External Ophthalmoplegia (CPEO), also known as Progressive External Ophthalmoplegia (PEO), is a type of eye disorder characterized by a loss of the muscle functions involved in eye and eyelid movement. CPEO can be caused by mutations in mitochondrial DNA. It typically manifests in young adults with bilateral and progressive ptosis as the most common presentation but can also present with difficulty swallowing (dysphagia) and general weakness of the skeletal muscles (myopathy), particularly in the neck, arms, or legs. CASE PRESENTATION: This is a case discussion of 3 cousins who presented to our clinic. A 23-year-old male with past surgical history (PSH) of ptosis repair 2 years ago presented with a chief complaint of nasal intonation for 1.5 years associated with difficulty swallowing. The patient also complained of nasal regurgitation of liquids. He denied any headaches, fever, seizures, weakness of arms or legs, urinary complaints or changes in bowel habits. Physical Examination was positive for facial muscle weakness, including an inability to lift eyebrows (Frontalis), inability to close eyes tightly (Orbicularis Oculi), corneal reflex absent bilaterally, difficulty clenching jaw (Masseter muscle), difficulty smiling (Zygomaticus major), inability to elevate upper lip (Zygomaticus minor). Another cousin of the first patient, a 25-year-old male with no past medical history, presented with complaints of nasal intonation for 2 years associated with difficulty swallowing. He denied a history of nasal regurgitation, headaches, fever, seizures, weakness, urinary complaints or changes in bowel habits. Physical Examination showed facial muscle weakness of the Frontalis muscle, Orbicularis Oculi muscle, Masseter Muscle, Zygomaticus Major, Zygomaticus Minor and absent corneal reflexes. A 28-year-old male, a cousin of the first two patients, presented with chief complaints of ptosis and nasal intonation for the last 8 years. He also complained of difficulty swallowing and nasal regurgitation of liquids. His physical examination showed facial muscle weakness, including frontalis muscle (inability to lift eyebrows), Orbicularis Oculi (inability to close eyes tightly), absent corneal reflexes bilaterally, Zygomaticus Major (difficulty smiling), and Zygomaticus Minor (inability to elevate upper lip). MRI brain and visual field of all the patients were normal. Differential diagnoses, including Grave’s disease, Myasthenia Gravis and Glioma, were ruled out. Due to financial reasons, muscle biopsy could not be pursued. Pedigree analysis revealed only males were affected, likely due to maternal inheritance, so the clinical diagnosis of CPEO was made. The patients underwent symptomatic management, including ptosis surgical correction for the third patient. CONCLUSION: Chronic Progressive External Ophthalmoplegia (CPEO), a rare case entity, occurs in young adults as a manifestation of mitochondrial myopathy. There are three modes of transmission- maternal transmission associated with mitochondrial point mutations, autosomal recessive, and autosomal dominant. CPEO can sometimes be difficult to diagnose, especially in asymmetric presentation. Therefore, it is crucial to keep it in differential diagnosis to avoid delay in diagnosis.

Keywords: neurology, chronic, progressive, ophthalmoplegia

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Authors: Alice Petzold, Alexandre Hassanin

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The number of giraffe species has been in focus of interest since the exploration of sub-Saharan Africa by European naturalists during the 18th and 19th centuries, as previous taxonomists, like Geoffroy Saint-Hilaire, Richard Owen or William Edward de Winton, recognized two or three species of Giraffa. For the last decades, giraffes were commonly considered as a single species subdivided into nine subspecies. In this study, we have re-examined available nuclear and mitochondrial data. Our genetic admixture analyses of seven introns support three species: G. camelopardalis (i.e., northern giraffes including reticulated giraffes), G. giraffa (southern giraffe) and G. tippelskirchi (Masai giraffe). However, the nuclear alignments show small variation and our phylogenetic analyses provide high support only for the monophyly of G. camelopardalis. Comparisons with the mitochondrial tree revealed a robust conflict for the position and monophyly of G. giraffa and G. tippelskirchi, which is explained firstly by a mitochondrial introgression from Masai giraffe to southeastern giraffe, and secondly, by gene flow mediated by male dispersal between southern populations (subspecies angolensis and giraffa). We conclude that current data gives only moderate support for three giraffe species and point out that additional nuclear data need to be studied to revise giraffe taxonomy.

Keywords: autosomal markers, Giraffidae, mitochondrial introgression, taxonomy

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Authors: Y. Ruchi, A. Prerna, S. Deepshikha

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Amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”. It is a neurodegenerative disease associated with degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord characterized by distal muscle weakness, atrophy, normal sensation, pyramidal signs and progressive muscular paralysis reflecting. ALS2 is a juvenile autosomal recessive disorder, slowly progressive, that maps to chromosome 2q33 and is associated with mutations in the alsin gene, a putative GTPase regulator. In this paper we have done homology modeling of alsin2 protein using multiple templates (3KCI_A, 4LIM_A, 402W_A, 4D9S_A, and 4DNV_A) designed using the Prime program in Schrödinger software. Further modeled structure is used to identify effective binding sites on the basis of structural and physical properties using sitemap program in Schrödinger software, structural and function analysis is done by using Prosite and ExPASy server that gives insight into conserved domains and motifs that can be used for protein classification. This paper summarizes the structural, functional and binding site property of alsin2 protein. These binding sites can be potential drug target sites and can be used for docking studies.

Keywords: ALS, binding site, homology modeling, neuronal degeneration

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Authors: Huong M. T. Nguyen, Hoa A. P. Nguyen, Chi V. Phan, Mai P. T. Nguyen, Ngoc D. Ngo, Van T. Ta, Hai T. Le

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Wilson’s disease is an autosomal recessive disorder of copper metabolism, which is caused by mutation in copper- transporting P-type ATPase (ATP7B). The mechanism of this disease is a failure of hepatic excretion of copper to the bile, and it leads to copper deposits in the liver and other organs. Most clinical symptoms of Wilson’s disease can present as liver disease and/or neurologic disease. Objective: The goal of the study is prenatal diagnosis for pregnant women at high risk of Wilson’s disease in Northern Vietnam. Material and method: Three probands with clinically diagnosed liver disease were detected in the mutations of 21 exons and exon-intron boundaries of the ATP7B gene by direct Sanger-sequencing. Prenatal diagnoses were performed by amniotic fluid sampling from pregnant women in the 16th-18th weeks of pregnancy after the genotypes of parents with the probands were identified. Result: A total of three different mutations of the probands, including of S105*, P1052L, P1273G, were detected. Among three fetuses which underwent prenatal genetic testing, one fetus was homozygote; two fetuses were carriers. Conclusion: Genetic testing provided a useful method for prenatal diagnosis, and is a basis for genetic counseling.

Keywords: ATP7B gene, genetic testing, prenatal diagnosis, pedigree, Wilson disease

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Authors: H. Bahbahani, H. Musa, F. Al Mathen

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The dromedary camels (Camelus dromedarius) are single-humped even-toed ungulates populating the African Sahara, Arabian Peninsula, and Southwest Asia. The genome of this desert-adapted species has been minimally investigated using autosomal microsatellite and mitochondrial DNA markers. In this study, the genomes of 33 dromedary camel samples from different parts of the Arabian Peninsula were sequenced using Illumina Next Generation Sequencing (NGS) platform. These data were combined with Genotyping-by-Sequencing (GBS) data from African (Sudanese) dromedaries to investigate the genomic relationship between African and Arabian Peninsula dromedary camels. Principle Component Analysis (PCA) and average genome-wide admixture analysis were be conducted on these data to tackle the objectives of these studies. Both of the two analyses conducted revealed phylogeographic distinction between these two camel populations. However, no breed-wise genetic classification has been revealed among the African (Sudanese) camel breeds. The Arabian Peninsula camel populations also show higher heterozygosity than the Sudanese camels. The results of this study explain the evolutionary history and migration of African dromedary camels from their center of domestication in the southern Arabian Peninsula. These outputs help scientists to further understand the evolutionary history of dromedary camels, which might impact in conserving the favorable genetic of this species.

Keywords: dromedary, genotyping-by-sequencing, Arabian Peninsula, Sudan

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Authors: Anupuma Raina, Ajay Parkash

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In forensic investigation, DNA analysis helps in the identification of a particular individual under investigation. A set of Short Tandem Repeats loci are widely used for individualization at a molecular level in forensic testing. STRs with tetrameric repeats of DNA are highly polymorphic and widely used for forensic DNA analysis. Identification of an individual became challenging for forensic examiners after Hematopoietic Stem Cell Transplantation. HSCT is a well-accepted and life-saving treatment to treat malignant and nonmalignant diseases. It involves the administration of healthy donor stem cells to replace the patient’s own unhealthy stem cells. A successful HSCT results in complete donor-derived cells in a patient’s hematopoiesis and hence have the capability to change the genetic makeup of the patient. Although an individual who has undergone HSCT and then committed a crime is a very rare situation, but not impossible. Keeping such a situation in mind, various biological samples like blood, buccal swab, and hair follicle were collected and studied after a certain interval of time after HSCT. Blood was collected from both the patient and the donor before the transplant. The DNA profile of both was analyzed using a short tandem repeat kit for autosomal chromosomes. Among all exhibits studied, only hair follicles were found to be the most suitable biological exhibit, as no donor DNA profile was observed for up to 90 days of study.

Keywords: chimerism, HSCT, STRs analysis, forensic identification

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Authors: Parisa Mansour

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Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among whites. It mostly affects the lungs, causing infections and inflammation that account for 90% of deaths in CF patients. Because of this high variability in clinical presentation and organ involvement, investigating treatment responses and evaluating lung changes over time is critical to preventing CF progression. High-resolution computed tomography (HRCT) greatly facilitates the assessment of lung disease progression in CF patients. Recently, artificial intelligence was used to analyze chest CT scans of CF patients. In this paper, we propose a convolutional neural network (CNN) approach to classify CF lung patterns in HRCT images. The proposed network consists of two convolutional layers with 3 × 3 kernels and maximally connected in each layer, followed by two dense layers with 1024 and 10 neurons, respectively. The softmax layer prepares a predicted output probability distribution between classes. This layer has three exits corresponding to the categories of normal (healthy), bronchitis and inflammation. To train and evaluate the network, we constructed a patch-based dataset extracted from more than 1100 lung HRCT slices obtained from 45 CF patients. Comparative evaluation showed the effectiveness of the proposed CNN compared to its close peers. Classification accuracy, average sensitivity and specificity of 93.64%, 93.47% and 96.61% were achieved, indicating the potential of CNNs in analyzing lung CF patterns and monitoring lung health. In addition, the visual features extracted by our proposed method can be useful for automatic measurement and finally evaluation of the severity of CF patterns in lung HRCT images.

Keywords: HRCT, CF, cystic fibrosis, chest CT, artificial intelligence

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Authors: Huong M. T. Nguyen, Hoa A. P. Nguyen, Mai P. T. Nguyen, Ngoc D. Ngo, Van T. Ta, Hai T. Le, Chi V. Phan

Abstract:

Wilson’s disease (WD) is an autosomal recessive disorder of the copper metabolism, which is caused by a mutation in the copper-transporting P-type ATPase (ATP7B). The mechanism of this disease is the failure of hepatic excretion of copper to bile, and leads to copper deposits in the liver and other organs. The ATP7B gene is located on the long arm of chromosome 13 (13q14.3). This study aimed to investigate the gene mutation in the Vietnamese patients with WD, and make a presymptomatic diagnosis for their familial members. Forty-three WD patients and their 65 siblings were identified as having ATP7B gene mutations. Genomic DNA was extracted from peripheral blood samples; 21 exons and exon-intron boundaries of the ATP7B gene were analyzed by direct sequencing. We recognized four mutations ([R723=; H724Tfs*34], V1042Cfs*79, D1027H, and IVS6+3A>G) in the sum of 20 detectable mutations, accounting for 87.2% of the total. Mutation S105* was determined to have a high rate (32.6%) in this study. The hotspot regions of ATP7B were found at exons 2, 16, and 8, and intron 14, in 39.6 %, 11.6 %, 9.3%, and 7 % of patients, respectively. Among nine homozygote/compound heterozygote siblings of the patients with WD, three individuals were determined as asymptomatic by screening mutations of the probands. They would begin treatment after diagnosis. In conclusion, 20 different mutations were detected in 43 WD patients. Of this number, four novel mutations were explored, including [R723=; H724Tfs*34], V1042Cfs*79, D1027H, and IVS6+3A>G. The mutation S105* is the most prevalent and has been considered as a biomarker that can be used in a rapid detection assay for diagnosis of WD patients. Exons 2, 8, and 16, and intron 14 should be screened initially for WD patients in Vietnam. Based on risk profile for WD, genetic testing for presymptomatic patients is also useful in diagnosis and treatment.

Keywords: ATP7B gene, mutation detection, presymptomatic diagnosis, Vietnamese Wilson’s disease

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Authors: Murat Emre, Zeynep Tufekcioglu

Abstract:

Objective: We describe a patient with late onset phenylketonuria which presented with rapidly progressive dementia and parkinsonism that were reversible after management. Background: Phenylketonuria is an autosomal recessive disorder due to mutations in the phenylalanine hydroxlase gene. It normally presents in childhood, in rare cases, however, it may have its onset in adulthood and may mimic other neurological disorders. Case description: A previously normal functioning, 59 year old man was admitted for blurred vision, cognitive impairment and gait difficulty which emerged over the past eight months. In neurological examination he had brisk reflexes, slow gait and left-dominant parkinsonism. Mini-mental state examination score was 25/30, neuropsychological testing revealed a dysexecutive syndrome with constructional apraxia and simultanagnosia. In cranial MRI there were bilateral diffuse hyper-intense lesions in parietal and occipital white matter with no significant atrophy. Electroencephalography showed diffuse slowing with predominance of teta waves. In cerebrospinal fluid examination protein level was slightly elevated (61mg/dL), oligoclonal bands were negative. Electromyography was normal. Routine laboratory examinations for rapidly progressive dementia and parkinsonism were also normal. Serum amino acid levels were determined to explore metabolic leukodystrophies and phenylalanine level was found to be highly elevated (1075 µmol/L) with normal tyrosine (61,20 µmol/L). His cognitive impairment and parkinsonian symptoms improved following three months of phenylalanine restricted diet. Conclusions: Late onset phenylketonuria is a rare, potentially reversible cause of rapidly progressive parkinsonism with dementia. It should be considered in the differential diagnosis of patients with suspicious features.

Keywords: dementia, neurology, Phenylketonuria, rapidly progressive parkinsonism

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Authors: E. A. Alaswad, H. M. Choudhry, F. Z. Filimban

Abstract:

Sickle Cell Anemia (SCA) is one type of blood diseases related to autosomal disorder. The sickle shaped red blood cells are the main cause of many problems in the blood vessels and capillaries. Aerva Javanica (J) and Ficus Palmata (P) are medicinal plants that have many popular uses and have been proved their efficacy. The aim of this study was to assess the antioxidants activity and the antisickling effect of J and P extractions. The period of this study, air-dried leaves of J, and P plants were ground and the active components were extracted by maceration in water (W) and methanol (M) as solvents. The antioxidants activity of JW, PW, JM, and PM were assessed by way of the radical scavenging method using 2,2-diphenyl-1-picrylhydrazyl (DPPH). To determine the antisickling effect of J and P extracts. 20 samples were collected from sickle cell anemia patients. Different concentrations of J and P extracts (200 and 110 μg/mL) were added on the sample and incubated. A drop of each sample was examined with light microscope. Normal and sickled RBCs were calculated and expressed as the percent of sickling. The stabilization effect of the extracts was measured by the osmotic fragility test for erythrocytes. The finding suggests as estimated by DPPH method, all the extracts showed an antioxidant activity with a significant inhibition of the DPPH radicals. PM has the least IC50% with 71.49 μg/ml while JM was the most with 408.49 μg/ml. Sickle cells treated with extracts at different concentrations significantly reduced the percentage of sickling compering to control samples. However, JM 200 μg/mL give the highest anti-sickling affect with 17.4% of sickling compared to control 67.5 of sickling while PM at 200 μg/mL showed the highest membrane cell stability. In a conclusion, the results showed that J and P extracts have antisickling effects. Therefore, the Aerva javanica and Ficus palmata may have a role in SCA management and a good impact on the patient's lives.

Keywords: Aerva javanica, antioxidant, antisickling, Ficus palmata, sickle cell anemia

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Authors: Eda Jazexhiu-Postoli, Gladiola Hoxha, Ada Simeoni, Sonila Biba

Abstract:

Background Neonatal hypotonia represents a commonly encountered issue in the Neonatal Intensive Care Unit and newborn nursery. The differential diagnosis is broad, encompassing chromosome abnormalities, primary muscular dystrophies, neuropathies and inborn errors of metabolism. Aim of study Our study describes some of the main clinical features of hypotonia in newborns and presents clinical cases of neonatal hypotonia we treated in our Neonatal unit in the last 3 years. Case reports Four neonates born in our hospital presented with hypotonia after birth, one preterm newborn 35-36 weeks of gestational age and three other term newborns (38-39 weeks of gestational age). Prenatal data revealed a decrease in fetal movements in both cases. Intrapartum meconium-stained amniotic fluid was found in 75% of our hypotonic newborns. Clinical features included inability to establish effective respiratory movements and need for resuscitation in the delivery room, respiratory distress syndrome, feeding difficulties and need for oro-gastric tube feeding, dysmorphic features, hoarse voice and moderate to severe muscular hypotonia. The genetic workup revealed the diagnosis of Autosomal Recessive Congenital Myasthenic Syndrome 1-B, Sotos Syndrome, Spinal Muscular Atrophy Type 1 and Transient Hypotonia of the Newborn. Two out of four hypotonic neonates were transferred to the Pediatric Intensive Care Unit and died at the age of three to five months old. Conclusion Hypotonia is a concerning finding in neonatal care and it is suggested by decreased intrauterine fetal movements, failure to establish first breaths, respiratory distress and feeding difficulties in the neonate. Prognosis is determined by its etiology and time of diagnosis and intervention.

Keywords: hypotonic neonate, respiratory distress, feeding difficulties, fetal movements

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Authors: Bindu I. Somarajan, Viney Gupta, Gagandeep Kaur Walia, Jasbir Kaur, Sunil Kumar, Shikha Gupta, Abadh K. Chaurasia, Dinesh Gupa, Abhinav Kaushik, Aditi Mehta, Vipin Gupta, Arundhati Sharma

Abstract:

Background: Juvenile onset primary open angle glaucoma (JOAG), affects individuals under the age of 40 years. Studies on a few families of JOAG, that led to the discovery of the Myocilin gene, reported the disease to have an autosomal dominant pattern of inheritance. However, sporadic forms of JOAG been seen to be more common in some populations. Most pathological homozygous mutations in the CYP1B1 gene associated with JOAG have been seen among sporadic cases. Given the higher prevalence of sporadic JOAG cases in our population, we aimed to look for common mutations E229K and R368H, the two most common variants in the CYP1B1 gene associated with glaucoma. Objective: To determine the frequency and evaluate genotype phenotype correlation of CYP1B1 E229K and R368H mutations in a cohort of 120 sporadic Juvenile open angle glaucoma patients.Methods: Unrelated JOAG patients whose first degree relatives had been examined and found to be unaffected were included in the study. The patients and their parents were screened for E229K and R368H mutations. The phenotypic characteristics were compared between probands with and with out these mutations by SPSS v16. Results: Out of 120 JOAG patients included in the study, the E229K mutation was seen in 9 probands (7.5%) and R368H in 7 (5.8%). The average age of onset of the disease (p=0.3) and the highest untreated IOP (p=0.4) among those carrying mutations was not significantly different from those who did not have these mutations. The proportion of probands with angle dysgenesis among those with E229K and R368H mutations was 70% (11 out of 16) in comparison to 65% (67 out of 104) of those who did not harbour these mutations (p=0.56). Similarly the probands with moderate to high myopia among those with E229K and R368H mutations was 20% (3 out of 16) in comparison to 18% (18 out of 104) of those who did not harbour these mutations(p=0.59). Conclusion: The frequency of E229K and R368H mutations of the CYP1B1 gene is low even among sporadic JOAG patients. Moreover there is no clinical correlation between the presence of these mutations and disease severity

Keywords: CYP1B1, gene, IOP, JOAG, mutation

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Authors: Maria L. G. Lourenço, Keylla H. N. P. Pereira, Viviane Y. Hibaru, Fabiana F. Souza, Joao C. P. Ferreira, Simone B. Chiacchio, Luiz H. A. Machado

Abstract:

Anasarca is generalized congenital edema that is often lethal. The condition is transmitted hereditarily and is autosomal dominant, with a racial predisposition in French Bulldogs and English Bulldogs. This study aims at reporting a case of anasarca treatment in neonates. The fetuses of a one year and six months old, primiparous English Bulldog mother were diagnosed with anasarca during an ultrasound examination performed at the 55th day of pregnancy and, therefore, an elective cesarean section was scheduled to prevent fetal dystocia. At birth, all puppies presented anasarca, and one of the six was stillborn. The newborns presented cyanosis, dyspnea, bradycardia, absent reflexes, low vitality scores (3/10), and hypothermia ( < 32ºC). The weight of the puppies at the time of birth varied between 347 and 373 grams, about 100 grams above the average weight estimated for the breed. Immediate neonatal care was applied with oxygen therapy via a mask, aminophylline (0.2 ml/100 g/PV/sublingual), and slow heating. After 10 minutes, there was a significant improvement in the neonatal parameters. The anasarca was treated with the drug furosemide, administered subcutaneously, at a dose of 0.2 mg per 100 grams of weight, every three hours. The stimulation for urination of newborns was performed every 30 minutes, and weight loss was monitored every 30 minutes. Five grams of potassium chloride were administered orally for every 30 grams of weight loss to counterbalance the loss of potassium caused by the diuretic medication. After 15 hours, the neonates reached the ideal weight for the breed, around 209 to 230 grams. In total, four neonates received five doses of furosemide, while one received six doses. The puppies are currently ten months old, healthy and neutered. Anasarca should not be ignored and is considered potentially lethal and an indication for euthanasia in all cases. Early intervention is of utmost importance for the survival of these patients.

Keywords: Walrus syndrome, congenital edema, water puppy syndrome, puppies

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Authors: Clara Franch de la Cal, Christopher J Morris, Michael McArthur

Abstract:

Cystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by abnormal transport of chloride and sodium across the lung epithelium, leading to thick and viscous secretions. Within which CF patients suffer from repeated bacterial pulmonary infections, with Pseudomonas aeru-ginosa (PA) eliciting the greatest inflammatory response, causing an irreversible loss of lung func-tion that determines morbidity and mortality. The cell wall of PA is a permeability barrier to many antibacterials and the rise of Mutli-Drug Resistant strains (MDR) is eroding the efficacy of the few remaining clinical options. In addition when PA infection becomes established it forms an antibi-otic-resistant biofilm, embedded in which are slow growing cells that are refractive to drug treat-ment. Making the development of new antibacterials a major challenge. This work describes the development of new type of nanoparticulate oligonucleotide antibacterial capable of tackling PA infections, including MDR strains. It is being developed to both block growth and prevent biofilm formation. These oligonucleotide therapeutics, Transcription Factor Decoys (TFD), act on novel genomic targets by capturing key regulatory proteins to block essential bacterial genes and defeat infection. They have been successfully transfected into a wide range of pathogenic bacteria, both in vitro and in vivo, using a proprietary delivery technology. The surfactant used self-assembles with TFD to form a nanoparticle stable in biological fluids, which protects the TFD from degradation and preferentially transfects prokaryotic membranes. Key challenges are to adapt the nanoparticle so it is active against PA in the context of biofilms and to formulate it for administration by inhalation. This would allow the drug to be delivered to the respiratory tract, thereby achieving drug concentrations sufficient to eradicate the pathogenic organisms at the site of infection.

Keywords: antibacterials, transcriptional factor decoys (TFDs), pseudomonas aeruginosa

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Authors: Ali Al Orf, Khawaja Bilal Waheed

Abstract:

Background and objective: Joubert syndrome (JS) is a rare, autosomal-recessive condition. Early recognition is important for management and counseling. Magnetic resonance imaging (MRI) can help in diagnosis. Therefore, we sought to evaluate clinical presentation and MRI findings in Joubert syndrome and related disorders. Method: A retrospective review of genetically proven cases of Joubert syndromes and related disorders was reviewed for their clinical presentation, demographic information, and magnetic resonance imaging findings in a period of the last 10 years. Two radiologists documented magnetic resonance imaging (MRI) findings. The presence of hypoplasia of the cerebellar vermis with hypoplasia of the superior cerebellar peduncle resembling the “Molar Tooth Sign” in the mid-brain was documented. Genetic testing results were collected to label genes linked to the diagnoses. Results: Out of 12 genetically proven JS cases, most were females (9/12), and nearly all presented with hypotonia, ataxia, developmental delay, intellectual impairment, and speech disorders. 5/12 children presented at age of 1 or below. The molar tooth sign was seen in 10/12 cases. Two cases were associated with other brain findings. Most of the cases were found associated with consanguineous marriage Conclusion and discussion: The molar tooth sign is a frequent and reliable sign of JS and related disorders. Genes related to defective cilia result in malfunctioning in the retina, renal tubule, and neural cell migration, thus producing heterogeneous syndrome complexes known as “ciliopathies.” Other ciliopathies like Senior-Loken syndrome, Bardet Biedl syndrome, and isolated nephronophthisis must be considered as the differential diagnosis of JS. The main imaging findings are the partial or complete absence of the cerebellar vermis, hypoplastic cerebellar peduncles (giving MTS), and (bat-wing appearance) fourth ventricular deformity. LimitationsSingle-center, small sample size, and retrospective nature of the study were a few of the study limitations.

Keywords: Joubart syndrome, magnetic resonance imaging, molar tooth sign, hypotonia

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Authors: Zainab S. Ahmed, Mohammed S. Ali, Nadia A. Elshiekh, Sami Adam Ibrahim, Ghada M. El-Tayeb, Ahmed H. Elsadig, Rihab A. Omer, Sofia B. Mohamed

Abstract:

Maple syrup urine (MSUD) is an autosomal recessive disease that causes a deficiency in the enzyme branched-chain alpha-keto acid (BCKA) dehydrogenase. The development of disease has been associated with SNPs in the DBT gene. Despite that, the computational analysis of SNPs in coding and noncoding and their functional impacts on protein level still remains unknown. Hence, in this study, we carried out a comprehensive in silico analysis of missense that was predicted to have a harmful influence on DBT structure and function. In this study, eight different in silico prediction algorithms; SIFT, PROVEAN, MutPred, SNP&GO, PhD-SNP, PANTHER, I-Mutant 2.0 and MUpo were used for screening nsSNPs in DBT including. Additionally, to understand the effect of mutations in the strength of the interactions that bind protein together the ELASPIC servers were used. Finally, the 3D structure of DBT was formed using Mutation3D and Chimera servers respectively. Our result showed that a total of 15 nsSNPs confirmed by 4 software (R301C, R376H, W84R, S268F, W84C, F276C, H452R, R178H, I355T, V191G, M444T, T174A, I200T, R113H, and R178C) were found damaging and can lead to a shift in DBT gene structure. Moreover, we found 7 nsSNPs located on the 2-oxoacid_dh catalytic domain, 5 nsSNPs on the E_3 binding domain and 3 nsSNPs on the Biotin Domain. So these nsSNPs may alter the putative structure of DBT’s domain. Furthermore, we detected all these nsSNPs are on the core residues of the protein and have the ability to change the stability of the protein. Additionally, we found W84R, S268F, and M444T have high significance, and they affected Leucine, Isoleucine, and Valine, which reduces or disrupt the function of BCKD complex, E2-subunit which the DBT gene encodes. In conclusion, based on our extensive in-silico analysis, we report 15 nsSNPs that have possible association with protein deteriorating and disease-causing abilities. These candidate SNPs can aid in future studies on Maple Syrup Urine Disease type II base in the genetic level.

Keywords: DBT gene, ELASPIC, in silico analysis, UCSF chimer

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Authors: N. C. van der Merwe, J. Oosthuizen, M. F. Makhetha, J. Adams, B. K. Dajee, S-R. Schneider

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Women representing high-risk breast cancer families, who tested negative for pathogenic mutations in BRCA1 and BRCA2, are four times more likely to develop breast cancer compared to women in the general population. Sequencing of genes involved in genomic stability and DNA repair led to the identification of novel contributors to familial breast cancer risk. These include BLM and PALB2. Bloom's syndrome is a rare homozygous autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia and is associated with breast cancer when in a heterozygous state. PALB2, on the other hand, binds to BRCA2 and together, they partake actively in DNA damage repair. Archived DNA samples of 66 BRCA1/2 negative high-risk breast cancer patients were retrospectively selected based on the presence of an extensive family history of the disease ( > 3 affecteds per family). All coding regions and splice-site boundaries of both genes were screened using High-Resolution Melting Analysis. Samples exhibiting variation were bi-directionally automated Sanger sequenced. The clinical significance of each variant was assessed using various in silico and splice site prediction algorithms. Comprehensive screening identified a total of 11 BLM and 26 PALB2 variants. The variants detected ranged from global to rare and included three novel mutations. Three BLM and two PALB2 likely pathogenic mutations were identified that could account for the disease in these extensive breast cancer families in the absence of BRCA mutations (BLM c.11T > A, p.V4D; BLM c.2603C > T, p.P868L; BLM c.3961G > A, p.V1321I; PALB2 c.421C > T, p.Gln141Ter; PALB2 c.508A > T, p.Arg170Ter). Conclusion: The study confirmed the contribution of pathogenic mutations in BLM and PALB2 to the familial breast cancer burden in South Africa. It explained the presence of the disease in 7.5% of the BRCA1/2 negative families with an extensive family history of breast cancer. Segregation analysis will be performed to confirm the clinical impact of these mutations for each of these families. These results justify the inclusion of both these genes in a comprehensive breast and ovarian next generation sequencing cancer panel and should be screened simultaneously with BRCA1 and BRCA2 as it might explain a significant percentage of familial breast and ovarian cancer in South Africa.

Keywords: Bloom Syndrome, familial breast cancer, PALB2, South Africa

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Authors: Priscila A. Bernardes, Marcos E. Buzanskas, Luciana C. A. Regitano, Ricardo V. Ventura, Danisio P. Munari

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The best linear unbiased predictor (BLUP) is a method commonly used in genetic evaluations of breeding programs. However, this approach can lead to higher inbreeding coefficients in the population due to the intensive use of few bulls with higher genetic potential, usually presenting some degree of relatedness. High levels of inbreeding are associated to low genetic viability, fertility, and performance for some economically important traits and therefore, should be constantly monitored. Unreliable pedigree data can also lead to misleading results. Genomic information (i.e., single nucleotide polymorphism – SNP) is a useful tool to estimate the inbreeding coefficient. Runs of homozygosity have been used to evaluate homozygous segments inherited due to direct or collateral inbreeding and allows inferring population selection history. This study aimed to evaluate runs of homozygosity (ROH) and inbreeding in a population of Nelore beef cattle. A total of 814 animals were genotyped with the Illumina BovineHD BeadChip and the quality control was carried out excluding SNPs located in non-autosomal regions, with unknown position, with a p-value in the Hardy-Weinberg equilibrium lower than 10⁻⁵, call rate lower than 0.98 and samples with the call rate lower than 0.90. After the quality control, 809 animals and 509,107 SNPs remained for analyses. For the ROH analysis, PLINK software was used considering segments with at least 50 SNPs with a minimum length of 1Mb in each animal. The inbreeding coefficient was calculated using the ratio between the sum of all ROH sizes and the size of the whole genome (2,548,724kb). A total of 25.711 ROH were observed, presenting mean, median, minimum, and maximum length of 3.34Mb, 2Mb, 1Mb, and 80.8Mb, respectively. The number of SNPs present in ROH segments varied from 50 to 14.954. The longest ROH length was observed in one animal, which presented a length of 634Mb (24.88% of the genome). Four bulls were among the 10 animals with the longest extension of ROH, presenting 11% of ROH with length higher than 10Mb. Segments longer than 10Mb indicate recent inbreeding. Therefore, the results indicate an intensive use of few sires in the studied data. The distribution of ROH along the chromosomes showed that chromosomes 5 and 6 presented a large number of segments when compared to other chromosomes. The mean, median, minimum, and maximum inbreeding coefficients were 5.84%, 5.40%, 0.00%, and 24.88%, respectively. Although the mean inbreeding was considered low, the ROH indicates a recent and intensive use of few sires, which should be avoided for the genetic progress of breed.

Keywords: autozygosity, Bos taurus indicus, genomic information, single nucleotide polymorphism

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