Autosomal Recessive Mode Of Inheritance Research Articles

ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons

Vaccinia-related kinase 1 (VRK1) is a gene which has been implicated in the pathological process of a broad range of neurodevelopmental disorders as well as neuropathies, such as Amyotrophic Lateral Sclerosis (ALS). Here we report a family presenting ALS in an autosomal recessive mode of inheritance, segregating with a homozygous missense mutation located in VRK1 gene (p.R321C; Arg321Cys). Proteomic analyses from iPSC-derived motor neurons identified 720 proteins eligible for subsequent investigation, and our exploration of protein profiles revealed significant enrichments in pathways such as mTOR signaling, E2F, MYC targets, DNA repair response, cell proliferation and energetic metabolism. Functional studies further validated such alterations, showing that affected motor neurons presented decreased levels of global protein output, ER stress and downregulation of mTOR signaling. Mitochondrial alterations also pointed to decreased reserve capacity and increased non-mitochondrial oxygen consumption. Taken together, our results present the main pathological alterations associated with VRK1 mutation in ALS.

Clinical profile of children with metabolic liver diseases presenting in a tertiary care hospital of Eastern India

Clinical profile of children with metabolic liver diseases presenting in a tertiary care hospital of Eastern India

Clinicopathological and pedigree investigation of a novel spinocerebellar neurological disease in juvenile Quarter Horses in North America.

In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. Twelve neurologically affected QH foals and the dams. Genomic DNA was isolated and pedigrees were manually constructed. All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.

Mutation of the Thap4 gene causes dwarfism and testicular anomalies in rats and mice.

The petit (pet) locus is associated with dwarfism, testicular anomalies, severe thymic hypoplasia, and high postnatal lethality, which are inherited in autosomal recessive mode of inheritance in rats with a Wistar strain genetic background. Linkage analysis localized the pet locus between 98.7Mb and 101.2Mb on rat chromosome 9. Nucleotide sequence analysis identified 2bp deletion in exon 2 of the Thap4 gene as the causative mutation for pet. This deletion causes a frameshift and premature termination codon, resulting in a truncated THAP4 protein lacking approximately two-thirds of the C-terminal side. Thap4 is expressed in various organs, including the testis and thymus in rats. To elucidate the biological function of THAP4 in other species, we generated Thap4 knockout mice lacking exon 2 of the Thap4 gene through genome editing. Thap4 knockout mice also exhibited dwarfism and small testis but did not show high postnatal lethality. Thymus weights of adult Thap4 knockout male mice were significantly higher compared to wild-type male mice. Although Thap4 knockout male mice were fertile, their testis contained seminiferous tubules with spermatogenesis and degenerative seminiferous tubules lacking germ cells. Additionally, we observed vacuoles in seminiferous tubules, and clusters of cells in the lumen in seminiferous tubules in Thap4 knockout male mice. These results demonstrate that spontaneous mutation of Thap4 gene in rats and knockout of Thap4 gene in mice both cause dwarfism and testicular anomalies. Thap4 gene in rats and mice is essential for normal testicular development, maintaining spermatogenesis throughout the entire region of seminiferous tubules.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population

BackgroundTo investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children’s Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry.MethodsWe selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS).ResultsOur study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes.ConclusionsIran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Особенности патологии органа зрения при орфанном синдроме Pierson вследствие мутации гена LAMB2 у детей: обзор литературы и клиническое наблюдение

Pierson syndrome is an orphan disease with an autosomal recessive mode of inheritance, characterized by combined pathology of the organ of vision, kidneys and central nervous system. Pierson syndrome is caused by a mutation in the LAMB2 gene, mapped on chromosome 3p21, encoding β2-laminin. The pathology of the organ of vision in Pierson syndrome in children is quite diverse. They are characterized by the presence of cataract, posterior lenticonus, iris hypoplasia, glaucoma, retinal detachment, etc. Microcoria (pupil diameter less than 2 mm) is also often observed due to atrophy of the pupillary dilator. The final diagnosis of Pierson syndrome can only be made based on the results of a molecular genetic study. Due to the severe lifethreatening renal manifestations of Pierson syndrome, for a long time the description of ophthalmological pathology was rather superficial. However, considering the high frequency and clinical severity of vision pathology in Pierson syndrome, it seems especially important to study in detail the features of the ocular phenotype in this disease. We have described a clinical observation of a child with Pierson syndrome, who was diagnosed with a missense mutation of the LAMB2 gene, a previously undescribed variant (rs143405268) in exon 18. The disease manifested itself as a combined pathology of the organ of vision, kidneys and the central nervous system. The ocular phenotype of the probands represented by microcoria, diffuse congenital cataract, and later by secondary glaucoma (after cataract surgery). Features of the renal phenotype of the proband were revealed – a horseshoe-shaped kidney, proteinuria not reaching the level of nephrotic syndrome, with preserved renal function. The peculiarity of this case of a child with Pierson syndrome is the absence of nephrotic syndrome in combination with the classic ocular phenotype with a previously undescribed variant of the LAMB2 gene mutation identified. Key words: pierson syndrome, LAMB 2, congenital cataract, microcoria, secondary glaucoma

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

Unraveling the genome: Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an inherited, autoinflammatory disease with a high prevalence in Middle Eastern and Mediterranean populations including Turks, Iranian, Spanish, Sephardic Jews, Arabs, and other Mediterranean ethnic groups. Autoinflammatory diseases are genetically predetermined disorders with multisystem effects primarily caused by defects in innate immunity. Although primarily known for an autosomal recessive mode of inheritance, there are increasing case reports associated with single Mediterranean fever (MEFV) mutation or dominant transmission. There have been over 300 variants identified in the MEFV gene; however, roughly 9-11 variants are responsible for the phenotypical expression seen with FMF. Symptoms include recurrent episodes of fever of unknown origin, abdominal, chest, or joint pain because of serosal inflammation. Persistent elevations in serum amyloid A can lead to complications like renal amyloidosis, kidney dysfunction, and end-stage kidney disease. Familial Mediterranean fever is diagnosed clinically using the Tel-Hashomer criteria and confirmed through genetic testing. Treatment includes initiation of colchicine with the goal of stopping attacks and preventing renal dysfunction and end-stage kidney disease. Genetic testing helps to identify the specific mutation allowing the provider to create a patient-specific treatment plan, monitor for complications such as renal amyloidosis, and enhance knowledge on the genetic heterogeneity and possible epigenetic factors.

Homozygous Mutations in GDAP1 and MFN2 Genes Resulted in Autosomal Recessive Forms of Charcot-Marie-Tooth Disease in Consanguineous Pakistani Families.

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease of peripheral nervous system diseases in which more than 100 genes and their mutations are associated. Two consanguineous families Dera Ghazi Khan (PAK-CMT1-DG KHAN) and Layyah (PAK-CMT2-LAYYAH) with multiple CMT-affected subjects were enrolled from Punjab province in Pakistan. Basic epidemiological data were collected for the subjects. Nerve conduction study (NCS) and electromyography (EMG) were performed for the patients. Whole-exome sequencing (WES) followed by Sanger sequencing was applied to report the genetic basic of CMT. The NCS findings revealed that sensory and motor nerve conduction velocities for both families were <38 m/s. EMG presented denervation, neuropathic motor unit potential, and reduced interference pattern of peripheral nerves. WES identified that a novel nonsense mutation (c. 226 G>T) in GADP1 gene and a previously known missense mutation in MFN2 gene (c. 334 G>A) cause CMT4A (Charcot-Marie-Tooth disease type 4A) in the PAK-CMT1-DG KHAN family and CMT2A (Charcot-Marie-Tooth disease type 2A) in the PAK-CMT2-LAYYAH family, respectively. Mutations followed Mendelian pattern with autosomal recessive mode of inheritance. Multiple sequence alignment by Clustal Omega indicated that mutation-containing domain in both genes is highly conserved, and in situ analysis revealed that both mutations are likely to be pathogenic. We reported that a novel nonsense mutation and a previously known missense mutation in GAPD1 gene and MFN2 gene, respectively, cause CMT in consanguineous Pakistani families.

Cardiomyopathy associated 5 (CMYA5) implicated as a genetic risk factor for radial hemimelia in Siamese cats.

The present study aimed to determine the inheritance pattern and genetic cause of congenital radial hemimelia (RH) in cats. Clinical and genetic analyses were conducted on a Siamese cat family (n = 18), including two siblings with RH. Radiographs were obtained for the affected kittens and echocardiograms of an affected kitten and sire. Whole genome sequencing was completed on the two cases and the parents. Genomic data were compared with the 99 Lives Cat Genome data set of 420 additional domestic cats with whole genome and whole exome sequencing data. Variants were considered as homozygous in the two cases of the siblings with RH and heterozygous in the parents. Candidate variants were genotyped by Sanger sequencing in the extended pedigree. Radiographs of the female kitten revealed bilateral absence of the radii and bowing of the humeri, while the male kitten showed a dysplastic right radius. Echocardiography suggested the female kitten had restrictive cardiomyopathy with a positive left atrial-to-aortic root ratio (LA:Ao = 1.83 cm), whereas hypertrophic cardiomyopathy was more likely in the sire, showing diastolic dysfunction using tissue Doppler imaging (59.06 cm/s). Twenty-two DNA variants were unique and homozygous in the affected kittens and heterozygous in the parents. Seven variants clustered in one chromosomal region, including two frameshift variants in cardiomyopathy associated 5 (CMYA5) and five variants in junction mediating and regulatory protein, P53 cofactor (JMY ), including a missense and an in-frame deletion. The present study suggested an autosomal recessive mode of inheritance with variable expression for RH in the Siamese cat family. Candidate variants for the phenotype were identified, implicating their roles in bone development. These genes should be considered as potentially causal for other cats with RH. Siamese cat breeders should consider genetically testing their cats for these variants to prevent further dissemination of the suspected variants within the breed.

A SACS deletion variant in Great Pyrenees dogs causes autosomal recessive neuronal degeneration.

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is a human neurological disorder characterized by progressive cerebellar ataxia and peripheral neuropathy. A recently recognized disorder in Great Pyrenees dogs is similarly characterized by widespread central nervous system degeneration leading to progressive cerebellar ataxia and spasticity, combined with peripheral neuropathy. Onset of clinical signs occurred in puppies as young as 4 months of age, with slow progression over several years. A multi-generation pedigree suggested an autosomal recessive mode of inheritance. Histopathology revealed consistent cerebellar Purkinje cell degeneration, neuronal degeneration in brainstem nuclei, widespread spinal cord white matter degeneration, ganglion cell degeneration, inappropriately thin myelin sheaths or fully demyelinated peripheral nerve fibers, and normal or only mild patterns of denervation atrophy in skeletal muscles. Genome-wide single nucleotide polymorphism (SNP) genotype data was collected from 6 cases and 26 controls, where homozygosity mapping identified a 3.3Mb region on CFA25 in which all cases were homozygous and all controls were either heterozygous or homozygous for alternate haplotypes. This region tagged the SACS gene where variants are known to cause ARSACS. Sanger sequencing of SACS in affected dogs identified a 4bp deletion that causes a frame shift and truncates 343 amino acids from the C terminus of the encoded sacsin protein (p.Val4244AlafsTer32). Our clinical and histopathological descriptions of this canine disorder contribute to the description of human ARSACS and represents the first naturally occurring large animal model of this disorder.

Searching for Effective Methods of Diagnosing Nervous System Lesions in Patients with Alström and Bardet-Biedl Syndromes.

Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators of nervous system changes occurring in patients with ALMS and BBS using optical coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) methods compared to a group of healthy subjects. The OCT results showed significantly lower macular thickness in the patient group compared to the control group (p = 0.002). The MRS study observed differences in metabolite levels between the study and control groups in brain areas such as the cerebellum, thalamus, and white matter. After summing the concentrations from all areas, statistically significant results were obtained for N-acetylaspartate, total N-acetylaspartate, and total creatine. Concentrations of these metabolites were reduced in ALMS/BBS patients by 38% (p = 0.0004), 35% (p = 0.0008), and 28% (p = 0.0005), respectively. Our results may help to understand the pathophysiology of these rare diseases and identify strategies for new therapies.

Dysferlinopathy in Tunisia: clinical spectrum, genetic background and prognostic profile

Dysferlinopathy is a rare group of hereditary muscular dystrophy with an autosomal recessive mode of inheritance caused by a mutation in the DYSF gene. It encodes for the dysferlin protein, which has a crucial role in multiple cellular processes, including muscle fiber membrane repair. This deficit has heterogeneous clinical presentations. In this study, we collected 20 Tunisian patients with a sex ratio of 1 and a median age of 50.5 years old (Interquartile range (IQR) = [36,5–54,75]). They were followed for periods ranging from 5 to 48 years. The median age at onset was 17 years old (IQR = [16,8–28,4]). Five major phenotypes were identified: Limb-girdle muscular dystrophy (LGMDR2) (35%), a proximodistal phenotype (35%), Miyoshi myopathy (10%), Distal myopathy with anterior tibial onset (DMAT) (10%), and asymptomatic HyperCKemia (10%). At the last evaluation, more than half of patients (55%) were on wheelchair. Loss of ambulation occurred generally during the fourth decade. After 20 years of disease progression, two patients with a proximodistal phenotype (10%) developed dilated cardiomyopathy and mitral valve regurgitation. Restrictive respiratory syndrome was observed in three patients (DMAT: 1 patient, proximodistal phenotype: 1 patient, LGMDR2: 1 patient). Genetic study disclosed five mutations. We observed clinical heterogeneity between families and even within the same family. Disease progression was mainly slow to intermediate regardless of the phenotype.

Autosomal dominant Zellweger spectrum disorder caused by de novo variants in PEX14 gene

PurposeZellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD. MethodsWe performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies. ResultsWe identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients’ fibroblasts. ConclusionOur finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.

The identification of AMZ2 as a candidate causative gene in a severe teratozoospermia patient characterized by vacuolated spermatozoa.

Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date. While several monogenic factors are linked to cephalic abnormalities, such as globozoospermia and macrozoospermia, the genetic cause of vacuolated spermatozoa remains inadequately described. Here, we analyzed whole-exome sequencing (WES) data for an individual from a consanguineous family with severely vacuolated spermatozoa. The analysis revealed a novel homozygous c.520A>G (p.Thr174Ala) variant in the archaelysin family metallopeptidase 2 (AMZ2), a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm. Multiple algorithms predicted this variant to be a damaging mutation. Consistent with an autosomal recessive mode of inheritance, this variant was inherited from heterozygous parental carriers. To investigate the potential pathogenicity of the identified variant, we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control. Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa. Our findings reveal a candidate causative gene for vacuolated spermatozoa.

BG10 A case of pachydermoperiostosis (primary hypertrophic osteoarthropathy)

Abstract We report a case of a 21-year-old man who was referred from the community with concern about persistent swollen and inflamed eyelids together with possible facial acne. He was known to have hypertrophic osteoarthropathy under the care of rheumatology for which he was on regular infliximab infusions. He had previously been treated with methotrexate (intolerant) azathioprine and adalimumab (lack of efficacy). He also had a long-standing history of inflammatory bowel disease and associated complications: iron-deficiency anaemia, previous choledochal cyst and biliary stricture, as well as previous deficiencies in vitamins B12, A and E. The patient was known to the genetics team, with prior genetic testing demonstrating that he is homozygous for a pathogenic SLC02A1 variant (c.1264_1265delAC). This gene encodes a prostaglandin transporter involved in mediating the uptake and clearance of prostaglandins in numerous tissues. On examination, he was found to have pronounced thickening of the facial skin, especially the forehead, alongside deep furrowing of the scalp. The eyelids were severely swollen and inflamed, with prominent straight eyelashes. There were milia present on the face predominantly on the brow and cheeks. There was clubbing of all digits on his hands and feet. The cutaneous findings were deemed all in keeping with pachydermoperiostosis. Pachydermoperiostosis, also known as primary/idiopathic hypertrophic osteoarthropathy, Touraine–Solente–Gole syndrome and Rosenfeld–Kloepfer syndrome, was first described by Friedrich in 1868. This is a rare condition, and both autosomal dominant and autosomal recessive modes of inheritance have been noted. The condition usually presents during puberty and the hallmark features are thickening and coarsening of the facial skin, periostosis and digital clubbing. Other cutaneous features can include seborrhoea with sebaceous hyperplasia, acne, hyperhidrosis and cutis verticis gyrata. Ocular manifestations include blepharoptosis, floppy eyelid syndrome, and hypertrophy of both the eyelids and palpebral conjunctiva. Crohn disease and multiple bone and joint issues are known features of the condition (Doshi D. Touraine–Solente–Gole syndrome. Orbit 2018; 37:97–101; Tabatabaei SA, Masoomi A, Soleimani M et al. Pachydermoperiostosis: a clinicopathological description. J Curr Ophthalmol 2019; 31:450–3). This reported case demonstrates both classic cutaneous and other organ system features of this rare genetic condition. It highlights the importance of being able to recognize all the associated findings when a patient presents with thickening of their facial skin and eyelids.

BG06 Beyond keratin: when simplex is not so simple

Abstract Epidermolysis bullosa simplex (EBS) is a heterogeneous, congenital, mucocutaneous fragility syndrome, characterized ultrastructurally by cleavage within the basal keratinocyte. Seventy-five per cent of cases are attributable to mutations in KRT5 and KRT14, the vast majority of which are dominant negative mutations, resulting in impaired keratin intermediate filament dynamics within the basal layer of the epidermis. The presenting phenotype, including extracutaneous manifestations and overall severity, is often closely linked to the underlying genetic mutation; however, genotype–­phenotype correlation is poorly resolved in a minority of cases, and there is an approximately additional 15% of patients in whom genetic abnormalities are not identified. However, recent advances in next-generation sequencing technologies have expanded the mutational database. We describe two cases of EBS with rare underlying mutations and distinct clinical phenotypes. A 46-year-old man presented with widespread blistering primarily affecting his hands, feet, elbows and knees since childhood. He had unaffected, consanguineous parents and one of his three siblings was affected. Other presenting features included dystrophic nails, focal plantar keratoderma, truncal mottled pigmentation and large areas of hypopigmentation on the back. We considered a diagnosis of ‘EBS with mottled pigmentation’, but the autosomal recessive mode of inheritance and dystrophic nails were atypical. DNA whole-exome sequencing (WES) and bidirectional Sanger sequencing revealed a novel homozygous PLEC mutation [c.94dupG p.(Ala32GlyfsTer3)]. Pathogenic PLEC variants are known to cause autosomal dominant EBS, the Ogna type (MIM131950), autosomal recessive EBS with muscular dystrophy (MIM226670) and autosomal recessive EBS with pyloric atresia (MIM612138). To date, our patient has not manifested any signs of progressive muscle weakness, but the presenting age can vary. The second patient was a 30-year-old woman who presented with blistering on her flexures, feet, hands and friction sites since the age of 4 months. She had unaffected, consanguineous parents and eight unaffected siblings. WES and confirmatory bidirectional Sanger sequencing identified a homozygous nonsense mutation in DST [c.3370C&amp;gt;T p.(Gln1124Ter)]. DST encodes the epithelial isoform of bullous pemphigoid antigen-1, present in the skin, muscle and neuronal tissues. Only 11 patients with DST mutation-induced EBS have been reported to date. The cutaneous phenotype is reported to be blisters, postinflammatory dyspigmentation, scarring, nail dystrophy, keratoderma and hyperhidrosis. If the affected exon is present in neuronal isoforms and neuronal tissue, neurological symptoms are expected. Unlike the patient reported elsewhere who harbours exactly the same mutation, our patient has reported no neurological issues to date. These cases highlight the importance of unravelling genotype–phenotype correlation in rare autosomal recessive forms of EBS, with possible implications for future prognosis and management.

Autosomal recessive hyposegmentation of granulocytes in Australian Shepherd Dogs indicates a role for LMBR1L in myeloid leukocytes.

Pelger-Huët anomaly (PHA) in humans is an autosomal dominant hematological phenotype without major clinical consequences. PHA involves a characteristic hyposegmentation of granulocytes (HG). Human PHA is caused by heterozygous loss of function variants in the LBR gene encoding lamin receptor B. Bi-allelic variants and complete deficiency of LBR cause the much more severe Greenberg skeletal dysplasia which is lethal in utero and characterized by massive skeletal malformation and gross fetal hydrops. HG phenotypes have also been described in domestic animals and homology to human PHA has been claimed in the literature. We studied a litter of Australian Shepherd Dogs with four stillborn puppies in which both parents had an HG phenotype. Linkage analysis excluded LBR as responsible gene for the stillborn puppies. We then investigated the HG phenotype in Australian Shepherd Dogs independently of the prenatal lethality. Genome-wide association mapped the HG locus to chromosome 27 and established an autosomal recessive mode of inheritance. Whole genome sequencing identified a splice site variant in LMBR1L, c.191+1G>A, as most likely causal variant for the HG phenotype. The mutant allele abrogates the expression of the longer X2 isoform but does not affect transcripts encoding the shorter X1 isoform of the LMBR1L protein. The homozygous mutant LMBR1L genotype associated with HG is common in Australian Shepherd Dogs and was found in 39 of 300 genotyped dogs (13%). Our results point to a previously unsuspected function of LMBR1L in the myeloid lineage of leukocytes.

A FANCA mutation carrier with enhanced toxicity to cancer directed treatment - A case report and review of literature

Chemotherapy and radiotherapy are backbones of cancer treatment. Genome instability syndromes are rare but an essential factor to be identified early in the treatment of malignancies. It can lead to the occurrence of multiple malignancies and impede treatment due to undue hypersensitivity, leading to extreme and often fatal toxicities. We, hereby, report a case of a middle-aged lady who was diagnosed with a carcinoma of the head and neck and planned for treatment with neoadjuvant chemotherapy followed by surgery or chemoradiation. However, she developed severe toxicity to all forms of treatment for cancer. Her gene-based panel screening test revealed a Fanconi anaemia, complementation group A (FANCA) gene abnormality which is associated with an autosomal recessive mode of inheritance. This case outlines the importance of considering the possibility and a high index of suspicion of a hereditary basis in cases of relatively early-onset malignancy before defining an oncological treatment strategy. The paucity of data except for case reports limits evidence-based management in such cases and requires a collective effort for treatment.

Spectrum of genetic disorders and gene variants in the United Arab Emirates national population: insights from the CTGA database.

Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 307 pathogenic/likely pathogenic variants from CTGA's Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.