Autosomal Recessive Mode Of Inheritance Research Articles

THE ULTRASTRUCTURAL STUDY OF THE SPINAL CORD AND THE DELTOID MUSCLE OF THE CLINICAL CASE OF THE VERDNIG-HOFFMANN SYNDROME

The Werdnig-Hoffmann syndrome is an infantile form of hereditary spinal progressive muscle atrophy with an autosomal recessive mode of inheritance with a frequency of 1 per 10,000 population. The data on the complex ultramicroscopic study of the spinal cord and deltoid muscle of a clinical case of Verdnig-Hoffmann syndrome in a newborn male child who died at the age of 1 month are given. Rubella virus patterns of the RNA were isolated in serum and spinal cord tissue samples. Changes in the structure of the spinal cord and deltoid muscle are described. An ultrastructural study showed the presence of a virus in the tissue of the spinal cord and vascular endothelial cells of the muscle. In the tissue of the spinal cord against the destruction of neurons was detected rubella virus. Viral particles were localized both in the cytoplasm of preserved oligodendrocytes and diffusely in destructively altered tissue of the spinal cord. The number of cells in the spinal cord tissue was reduced, the structure of their mitochondria was disturbed, and vacuolization of the cytoplasm was detected. For myelin fibers there is inherent heterogeneity of the thickness of the membranes, uneven distribution, deformation of the contours, and variability of diameters. Myelin fibers stratified, fragmented, osmiophilia lost. In the study of muscle samples prevailed destructively modified muscle fibers. At the same time, against the background of an unevenly pronounced atrophy of muscle fibers, the reproduction of the rubella virus in the cytoplasm of capillary endotheliocytes and pericytes of muscle vessels was detected. The etiological role of the rubella virus in the onset of the clinical symptoms constituting spinal muscular atrophy syndrome as a variant of congenital rubella has been suggested. .

Rare mutation of the CCNO gene in patients with primary ciliary dyskinesia

Primary ciliary dyskinesia is a rare genetically determined pathology leading to the development of chronic inflammatory lesions of the respiratory system in children, impaired fertile function in older patients. The disease is characterized by an autosomal recessive mode of inheritance with marked genetic heterogeneity. The article describes clinical observation of a patient – carrier of a rare mutation and describes the features of this case.Conflict of interest: The authors of this article confirmed the lack of conflict of interest and financial support, which should be reported.

A PLN nonsense variant causes severe dilated cardiomyopathy in a novel autosomal recessive inheritance mode

BackgroundPathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode. MethodsWe performed high-depth targeted next-generation sequencing using a cardiomyopathy-panel containing 80 disease-related genes in 650 unrelated patients with non-ischemic cardiomyopathy to identify potential pathogenic PLN variants. To comprehensively evaluate the genetic cause of the proband and his pedigree, whole-exome sequencing and Sanger sequencing were performed. ResultsA novel homozygous nonsense variant (p.Glu2Ter, c.4G>T) in PLN was identified in a 36-year-old male suffering from dilated cardiomyopathy with severe heart failure. No more cardiomyopathy-causing variant or likely pathogenic copy number variation was identified. This variant was not detected in 800 unrelated healthy controls. Furthermore, the variant is not in the Exome Aggregation Consortium or the Genome Aggregation databases. Western blots showed that this variant significantly reduced the expression of phospholamban. Furthermore, in pedigree analysis, we found that all five heterozygous PLN-p.Glu2Ter carriers (including four elder relatives) had normal heart size and cardiac function, which revealed a novel autosomal recessive inheritance mode. ConclusionsOur study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.

Evaluation of MYORG mutations as a novel cause of primary familial brain calcification.

Very recently, the MYORG gene was identified as a novel causative gene for autosomal-recessive primary familial brain calcification. To investigate the clinical, genetic, and neuroradiological characteristics of primary familial brain calcification patients with biallelic MYORG mutations in China. We collected clinical and neuroradiological data of 169 Chinese patients with primary familial brain calcification, including 151 sporadic patients and 18 patients from 13 families compatible with an autosomal-recessive mode of inheritance. Mutational analysis of MYORG was performed in the cohort. We identified four, including three novel, MYORG mutations segregating in four families with 5 patients: one nonsense mutation (c.1431C>A, p.Y477*), one missense mutation (c.687G>T, p.W229C), and two nonframeshift indels (c.348_349insCTGGCCTTCCGC, p.116_117insLAFR; c. 428_442delTGCACTTCTTCATCC, p.143_147delLHFFI). The 12-base-pair insertion, c.348_349insCTGGCCTTCCGC, was found in either homozygous or heterozygous state in 2 probands of our cohort and another Chinese primary familial brain calcification patient previously reported on in the literature. Haplotype analysis of our patients harboring the insertion indicated a founder effect in the ethnic Han Chinese population. To date, biallelic MYORG mutations have been reported in 17 patients (including our cohort). Most patients were symptomatic (13 of 17; 76.5%), and the most recurrent symptoms were movement disorders (10 of 17; 58.8%), cognitive decline (7 of 17; 41.2%), and cerebellar symptoms (6 of 17; 35.3%). All patients had calcifications on comprehensive cranial CT, most frequently located in the basal ganglia (17 of 17; 100%), cerebellum (17 of 17; 100%), subcortical white matter (14 of 17; 82.4%), and thalamus (13 of 17; 76.5%). We confirmed MYORG as a novel causative gene for primary familial brain calcification and further expanded the mutational and phenotypic spectrum of MYORG-related primary familial brain calcification. © 2018 International Parkinson and Movement Disorder Society.

Congenital Aspirin-like Defect As a Result of Autosomal Recessive Variants in PTGS1

Inherited defects of platelet function disorders are rare and difficult to diagnose due to lack of standardized platelet tests. An aspirin-like platelet defect is characterised by reduced thromboxane A2 (TXA2) signalling due to a defect in the arachidonic acid (AA) pathway in platelets. Patients with aspirin-like defect present with mild to moderate bleeding symptoms and impaired platelet aggregation responses to AA and ADP. This is similar to the irreversible effect of aspirin on platelets, which is mediated through inhibition of prostaglandin H synthase-1 also known as cyclooxygenase-1 (PTGS1/COX1). We for the first time report platelet function disorders due to autosomal recessive inheritance of variants in PTGS1.In a total of 3563 cases with bleeding disorders, comprising 1169 whole genome sequenced probands of the BRIDGE-BPD study and 2394 panel sequenced index cases of the ThromboGenomics cohort, we identified 15 unrelated cases of each cohort with an aspirin-like platelet function defect. Two of these cases had rare a variants in PTGS1, the gene encoding COX-1, which catalyses the conversion of arachidonic acid to prostaglandin H2. The first case presented with epistaxis and peri-operative bleeding. She had reduced platelet aggregation responses to arachidonic acid, ADP, collagen and epinephrine. Incubation of control blood with collagen resulted in enhanced levels of thromboxane B2, PGD2, PGE2, 11-HETE and 15-HETE which was absent in the index case.We identified a homozygous missense variant in PTGS1, p.Trp322Ser with a Combined Annotation Dependant Depletion Score (CADD) of 31.0. This variant was absent from GnomAD. The variant co-segregated in an autosomal recessive inheritance mode, with aspirin-like defect phenotype in the seven family members who were investigated. PTGS1 was not expressed on the platelets by western blot. Immunophenotyping demonstrated absence on the platelet surface but presence on neutrophils. The second case of the presented with menorrhagia, nosebleeds, easy bleeding and bruising. She had reduced aggregation responses to arachidonic acid, ADP, collagen and epinephrine. We identified two variants in cis: a splice-donor variant (g. 125133553 T>A), CADD 24.3; and an upstream non-coding variant (g. 125132069 C>G), CADD 16.63. The frequency of these variants were respectively; 1.7 x 10-5 and 8 x 10-3 in GnomAD. Platelet RNA and protein expression studies in the propositus revealed alternative splicing with the generation of a smaller protein due the splice variant. In contrast, the non coding variant had no effect on promoter or enhancer activity and therefore, is likely benign. In this case, the mode of inheritance is autosomal dominant with a dominant negative effect, which has been reported previously. For the other 13 cases of the Bridge-BPD study we also interrogated the non-coding space and interactors in the arachidonic acid pathway, none of which had genetic variants explaining the phenotype. For the 15 ThromboGenomics cohort cases because they were sequenced on targeted platform similar investigations could not take place. These cases could have a non inherited cause for the platelet defect or it is also permissible that variation in a hitherto undefined pathways unique to individual cases might be causal.In conclusion, we for the first time report autosomal recessive inheritance of variants in PTGS1 as cause for a rare inherited bleeding disorder. The effect of the mutation are selective loss of expression of PTGS1 within platelets and decreased enzyme function. Two previous reports demonstrated autosomal dominant inheritance. The first demonstrated autosomal dominant inheritance of variants in PTGS1 as modifier in a well characterized family with haemophilia A and platelet function disorder (Nance et al JTH 2016). The second reported rare heterozygous variants in PTGS1 in two cases with a bleeding tendency which was not further specified in the report (Bastida et al Haematologica 2018). DisclosuresLaffan:Pfizer: Honoraria; Roche: Consultancy, Speakers Bureau.

Evidence for an autosomal recessive pattern of inheritance in Keratitis-ichthyosis-deafness (KID) syndrome: Exome sequencing reveals a novel homozygous GJB2 mutation

GJB2 encodes for connexin26 (Cx26), a small transmembrane protein component of the gap junction, which is essential for cellular communication in many epithelial cells. Mutations in GJB2 cause autosomal recessive and dominant non-syndromic hearing loss. Few mutations with a dominant transmission have been also linked to syndromic forms affecting the cochlea in combination with the epidermis. The severity and type of the resulting hyperproliferative epidermal disorders are however quite heterogeneous.The purpose of this study was to identify the genetic cause of a rare ectodermal dysplasia, keratitis-ichthyosis-deafness (KID) syndrome in three siblings of Saudi Arabian origin, born to first-cousin healthy parents. The affected presented with the classic phenotypic triad of KID syndrome including diffuse hyperkeratotic erythroderma, neurosensory hearing loss and vascularizing keratitis. Several other features were susceptibility to infections, dental dysplasia, hypohydrosis, growth delay and short stature. Exome sequencing revealed a missense GJB2 mutation (NM_004004: c.244A > G; p.Ile82Val), which is pathogenic in the homozygous state. We present evidence that KID syndrome can be caused by a homozygous GJB2 mutation and demonstrate an autosomal recessive mode of inheritance for the first time at a molecular level.The spectrum of skin manifestations associated with gap junction gene mutations is still growing, particularly in the case of Cx26. Our findings add to the list of pathogenic variants associated with this condition, and contribute to an insight into the genotype-phenotype correlations of Cx26 mutations, thus elucidating the function of different regions of the protein and further add to the widely diverging associated phenotypes.

IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences.

By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.

A rare case of skin blistering and esophageal stenosis in the course of epidermolysis bullosa - case report and literature review

BackgroundEpidermolysis bullosa (EB) constitutes a heterogenous group of rare multisystem genetically transmitted disorders comprising several blistering muco-cutaneous diseases with a monogenic basis and either autosomal dominant or autosomal recessive mode of inheritance. EB manifestation is not only limited to the skin. Systemic signs might involve the nose, ear, eye, genitourinary tract and upper gastrointestinal tract. The presence of particular symptoms is directly determined by a type of altered skin protein. Gastrointestinal manifestation of EB is most commonly reflected by esophageal stenosis due to recurrent esophageal blistering, followed by consequent scarring.Case presentationHere we present a case of a man with dystrophic EB and dysphagia, skin blistering, joints contractures and missing nails. To our knowledge, the presented man is the oldest one diagnosed with EB living in Poland.ConclusionsManagement of an esophageal stricture in such circumstances is based on endoscopic dilatation. However, in most severe cases, placement of a gastrostomy tube is required. Despite great advances in medicine, a targeted therapy in the course of EB has not been established yet.

A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis\xa0congenita in a Chinese Han family

BackgroundDyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. Cells from patients with DC exhibit short telomere. The genetic basis of the majority of DC cases remains unknown.MethodsA 2 generational Chinese Han family with DC was studied using targeted capture and next-generation sequencing to identify the underlying DC-related mutations.ResultsIn this study, we identified a unique homozygous WD repeat containing antisense to TP53 (WRAP53) Arg298Trp mutation in the proband with DC and heterozygous WRAP53 Arg298Trp mutations in his asymptomatic, consanguineous parents and his sister, indicating an autosomal recessive inheritance mode. The proband with the homozygous WRAP53 Arg298Trp mutation had short telomere, classic clinical symptoms, and no response to danazol, glucocorticoid or cyclosporin A.ConclusionsThus, we reported for the first time that a unique homozygous WRAP53 mutation site underlies the development of DC.

Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders

BackgroundMany of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies.MethodsWe undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents’ DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available.ResultsThe diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified.ConclusionsFor the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions.

Hereditary cataracts in Russian Blue cats.

The purpose of this study was to investigate the prevalence of cataracts in the Russian Blue breed of cats in Sweden, and to describe the clinical appearance of this presumed inherited form of cataract. A total of 66 Russian Blue cats were examined in Sweden, between March and October 2014, using standard examination techniques. The examined cats were between 3 months and 14 years of age. Pedigrees were collected from all examined cats for genetic studies. Mild-to-severe forms of mainly bilateral cataracts were observed in 22/66 examined Russian Blue cats of both sexes. Two affected cats were <1 year of age. The most frequently observed appearance of a cataract was a small triangular, Y-shaped or circular opacity at the border of the posterior nucleus and the anterior part of the posterior cortex, which caused no observable visual impairment. More extended forms were observed in 6/22 cats, with involvement of both the nucleus and either the entire cortex or parts of the posterior and/or anterior cortex. Visual impairment or blindness was observed in the latter six cases. Pedigree analyses indicated a simple autosomal recessive mode of inheritance for the defect, although a dominant mode with incomplete penetrance could not be excluded. This study indicates that the Russian Blue breed of cat is affected by hereditary cataracts. The high prevalence in young cats and the characteristic location of the most frequently observed defect in the study suggest an early onset type of cataract. The breeders should be aware of this defect and have their cats examined by a veterinary ophthalmologist before breeding of an individual Russian Blue cat is considered.

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic...

The impact of consanguinity on the frequency of inborn errors of metabolism

Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders present in all ethnic groups. We investigated the frequency of consanguinity among parents of newborns with IEM diagnosed by neonatal screening.Data were obtained from 15years of expanded newborn screening for selected IEM with autosomal recessive mode of inheritance, a national screening program of newborns covering the period from 2002 until April 2017. Among the 838,675 newborns from Denmark, the Faroe Islands and Greenland, a total of 196 newborns had an IEM of whom 155 from Denmark were included in this study. These results were crosschecked against medical records. Information on consanguinity was extracted from medical records and telephone contact with the families.Among ethnic Danes, two cases of consanguinity were identified in 93 families (2.15%). Among ethnic minorities there were 20 cases of consanguinity among 33 families (60.6%). Consequently, consanguinity was 28.2 times more frequent among descendants of other geographic place of origin than Denmark. The frequency of consanguinity was conspicuously high among children of Pakistani, Afghan, Turkish and Arab origin (71.4%). The overall frequency of IEM was 25.5 times higher among children of Pakistani, Turkish, Afghan and Arab origin compared to ethnic Danish children (5.35:10,000 v 0.21:10,000). The frequency of IEM was 30-fold and 50-fold higher among Pakistanis (6.5:10,000) and Afghans (10.6:10,000), respectively, compared to ethnic Danish children.The data indicate a strong association between consanguinity and IEM. These figures could be useful to health professionals providing antenatal, pediatric, and clinical genetic services.

An autosomal recessive mutation in SCL24A4 causing enamel hypoplasia in Samoyed and its relationship to breed-wide genetic diversity

BackgroundPure breeding of dogs has led to over 700 heritable disorders, of which almost 300 are Mendelian in nature. Seventy percent of the characterized mutations have an autosomal recessive mode of inheritance, indicative of positive selection during bouts of inbreeding primarily for new desired conformational traits. Samoyed suffer from several common complex genetic disorders, but up to this time only two X-linked and one autosomal dominant disorder have been identified. Previous studies based on pedigrees and SNP arrays have concluded that Samoyed breeders have done a good job in maintaining genetic diversity and avoiding excessive inbreeding. This may explain why autosomal recessive disorders have not occurred to the extent observed in many other breeds. However, an enamel hypoplasia analogous to a form of autosomal recessive amelogenesis imperfecta (ARAI) in humans has been recently characterized in Samoyed, although the causative mutation appears to have existed for three or more decades. The rise of such a mutation indicates that bouts of inbreeding for desired conformational traits are still occurring despite an old and well-defined breed standard. Therefore, the present study has two objectives: 1) measure genetic diversity in the breed using DNA and short tandem repeats (STR), and 2) identify the exact mutation responsible for enamel hypoplasia in the breed, possible explanations for its recent spread, and the effect of eliminating the mutation on existing genetic diversity.ResultsThe recent discovery of an autosomal recessive amelogenesis imperfecta (ARAI) in Samoyed provides an opportunity to study the mutation as well as genetic factors that favored its occurrence and subsequent spread. The first step in the study was to use 33 short tandem repeat (STR) loci on 25/38 autosomes and seven STRs across the dog leukocyte antigen (DLA) class I and II regions on CFA12 to determine the DNA-based genetic profile of 182 individuals from North America, Europe and Australia. Samoyed from the three continents constituted a single breed with only slight genetic differences. Breed-wide genetic diversity was low, most likely from a small founder population and subsequent artificial genetic bottlenecks. Two alleles at each autosome locus occurred in 70–95% of the dogs and 54% of alleles were homozygous. The number of DLA class I and II haplotypes was also low and three class I and two class II haplotypes occurred in 80–90% of individuals. Therefore, most Samoyed belong to two lines, with most dogs possessing a minority of existing genetic diversity and a minority of dogs containing a majority of diversity. Although contemporary Samoyed lack genetic diversity, the bulk of parents are as unrelated as possible with smaller subpopulations either more inbred or outbred than the total population. A familial disorder manifested by hypocalcification of enamel has been recently identified. A genome wide association study (GWAS) on seven affected and five unrelated healthy dogs pointed to a region of extended homozygosity on Canis familiaris autosome 8 (CFA8). The region contained a gene in the solute carrier 24 family (SCL24A4) that encodes a protein involved in potassium dependent sodium/calcium exchange and transport. Mutations in this gene were recently found to cause a similar type of enamel hypoplasia in people. Sequencing of this candidate gene revealed a 21 bp duplication in exon 17. A test for the duplication was in concordance with the disease phenotype. The exact incidence of affected dogs is unknown, but 12% of the 168 healthy dogs tested were heterozygous for the mutation. This population was biased toward close relatives, so a liberal estimate of the incidence of affected dogs in the breed would be around 3.6/1000. Theoretical calculations based on the comparison of the whole population with a population devoid of carriers indicated that eliminating the trait would not affect existing genetic diversity at this time.ConclusionsThe contemporary Samoyed, like many other breeds, has retained only a small portion of the genetic diversity that exists among all dogs. This limited genetic diversity along with positive genetic selection for desirable traits has led to at least three simple non-recessive genetic disorders and a low incidence of complex genetic traits such as autoimmune disease and hip dysplasia. Unlike many other pure breeds, the Samoyed has been spared the spate of deleterious autosomal recessive traits that have plagued many other pure breeds. However, ARAI due to a mutation in the SCL24A4 gene has apparently existed in the breed for several decades but is being increasingly diagnosed. The increase in diseased dogs is most likely due to a period of intensified positive selection for some desired conformational trait. A genetic test has been developed for identifying the mutation carriers which will enable the breeders to eliminate enamel hypoplasia in Samoyed by selective breeding and it appears that this mutation can be eliminated now without loss of genetic diversity.

OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism.

We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G). The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5’-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1). Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2) in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5’-splice site of the first intron of the canine OCA2 gene.

P.361 - McArdle Disease: Clinical, biochemical and molecular genetic analysis of 58 patients

McArdle disease is a common metabolic myopathy with autosomal recessive mode of inheritance. A frequent mutation p.Arg50Ter in the myophosphorylase gene is reported in patients with McArdle disease. We performed a systemic clinical, biochemical and molecular genetic analysis of 58 Caucasian patients (31 males and 27 females; mean age at diagnosis: 37 years) with McArdle disease. Clinically, all patients reported exercise induced myalgia and fatigue. However, permanent weakness was reported only in 45% patients. Twenty-one percentage patients had family history of McArdle disease. In 86% patients, the age of onset was in childhood (0–12 years). Myophosphorylase activity measured in all 18 available patients was highly reduced (mean: 0.17 U/g Tissue; Normal: 12–61). Molecular genetic analysis showed the common p. Arg50Ter mutation in 67% patients (25 homozygotes and 14 heterozygotes) with an allele frequency of 55%. The other frequent mutations identified were p.Arg270Ter (allele frequency: 6%) followed by c.2262delC and p.Met1Val (allele frequencies: 3%). Apart from these mutations, 25 other rare mutations were also identified. Three of these rare mutations were identified in two or more than two unrelated patients. A genotype-phenotype correlation could not be established as so many different genotypes were observed and all our patients did present with signs of exercise intolerance that is typical in McArdle disease. Moreover, despite different genotypes, the enzyme activity was highly reduced in all available patients. Present analysis shows an enormous genetic heterogeneity in McArdle disease with 28 rare or private mutations. However, high sensitivity of p.Arg50Ter mutation analysis emphasizes detection of this mutation as the first step of diagnosis in McArdle disease.

Ichthyosis fetalis in Polled Hereford and Shorthorn calves

Inherited forms of ichthyosis, or generalized scaling of the skin, have been reported in many animal species, including cattle, and are characterized by an autosomal recessive mode of inheritance. We investigated 2 calves affected with ichthyosis fetalis, a Polled Hereford and a Shorthorn. Both cases had hard white plaques on the skin consistent with excessive keratinization. This was confirmed by histopathology, which showed severe diffuse epidermal and follicular orthokeratotic hyperkeratosis. The known mutation (H1935R) in gene ABCA12, responsible for ichthyosis fetalis in Chianina cattle, was shown to be absent in both affected calves and their obligate heterozygous parents. These molecular findings indicate that allelic heterogeneity exists for this condition in cattle.

Two Variants inSLC24A5Are Associated with “Tiger-Eye” Iris Pigmentation in Puerto Rican Paso Fino Horses

A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino (PRPF) horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study (GWAS) with 24 individuals identified a locus on ECA 1 reaching genome-wide significance (Pcorrected = 1.32 × 10−5). This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium/Calcium Exchanger), Member 5 (SLC24A5), with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism (OCA) type 6 (OCA6), which is characterized by dilute skin, hair, and eye pigmentation, as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a nonsynonymous mutation in exon 2 (p.Phe91Tyr) of SLC24A5 (called here Tiger-eye 1), which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628 bp deletion encompassing all of exon 7 of SLC24A5 (c.875-340_1081+82del), which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye-associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds not known to have the tiger-eye phenotype. Here, we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2) does not appear to cause ocular anomalies or a change in coat color in the PRPF horse.

A variation in PANK2 gene is causing Pantothenate kinase-associated Neurodegeneration in a family from Jammu and Kashmir \u2013 India

Pantothenate kinase-associated neurodegeneration is a rare hereditary neurodegenerative disorder associated with nucleotide variation(s) in mitochondrial human Pantothenate kinase 2 (hPanK2) protein encoding PANK2 gene, and is characterized by symptoms of extra-pyramidal dysfunction and accumulation of non-heme iron predominantly in the basal ganglia of the brain. In this study, we describe a familial case of PKAN from the State of Jammu and Kashmir (J&K), India based on the clinical findings and genetic screening of two affected siblings born to consanguineous normal parents. The patients present with early-onset, progressive extrapyramidal dysfunction, and brain Magnetic Resonance imaging (MRI) suggestive of symmetrical iron deposition in the globus pallidi. Screening the PANK2 gene in the patients as well as their unaffected family members revealed a functional single nucleotide variation, perfectly segregating in the patient’s family in an autosomal recessive mode of inheritance. We also provide the results of in-silico analyses, predicting the functional consequence of the identified PANK2 variant.

Primary Immunodeficiency Diseases in Highly Consanguineous Populations from Middle East and North Africa: Epidemiology, Diagnosis, and Care

Middle East and North Africa region (MENA)1 populations are of different ethnic origins. Consanguineous marriages are common practice with an overall incidence ranging between 20 and 50%. Primary immunodeficiency diseases (PIDs) are a group of heterogeneous genetic disorders caused by defects in the immune system that predisposes patients to recurrent infections, autoimmune diseases, and malignancies. PIDs are more common in areas with high rates of consanguineous marriage since most have an autosomal recessive mode of inheritance. Studies of PIDs in the region had contributed into the discovery and the understanding of several novel immunodeficiency disorders. Few MENA countries have established national registries that helped in estimating the prevalence and defining common PID phenotypes. Available reports from those registries suggest a predominance of combined immunodeficiency disorders in comparison to antibody deficiencies seen in other populations. Access to a comprehensive clinical immunology management services is limited in most MENA countries. Few countries had established advanced clinical immunology service, capable to provide extensive genetic testing and stem cell transplantation for various immunodeficiency disorders. Newborn screening for PIDs is an essential need in this population considering the high incidence of illness and can be implemented and incorporated into existing newborn screening programs in some MENA countries. Increased awareness, subspecialty training in clinical immunology, and establishing collaborating research centers are necessary to improve patient care. In this review, we highlight some of the available epidemiological data, challenges in establishing diagnosis, and available therapy for PID patients in the region.