Autosomal Recessive Mode Of Inheritance Research Articles

SLC25A12 Missense Variant in Nova Scotia Duck Tolling Retrievers Affected by Cerebellar Degeneration-Myositis Complex (CDMC).

We investigated two litters of distantly related Nova Scotia Duck Tolling Retrievers (NSDTR), of which four puppies were affected by cerebellar signs with or without neuromuscular weakness. The phenotype was termed cerebellar degeneration—myositis complex (CDMC). We suspected a heritable condition and initiated a genetic analysis. The genome of one affected dog was sequenced and compared to 565 control genomes. This search yielded a private protein-changing SLC25A12 variant in the affected dog, XM_038584842.1:c.1337C>T, predicted to result in the amino acid change XP_038440770.1:(p.Pro446Leu). The genotypes at the variant co-segregated with the phenotype as expected for a monogenic autosomal recessive mode of inheritance in both litters. Genotyping of 533 additional NSDTR revealed variant allele frequencies of 3.6% and 1.3% in a European and a North American cohort, respectively. The available clinical and biochemical data, together with current knowledge about SLC25A12 variants and their functional impact in humans, mice, and dogs, suggest the p.Pro446Leu variant is a candidate causative defect for the observed phenotype in the affected dogs.

Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency

BackgroundIsolated sulfite oxidase deficiency (ISOD) is a rare type of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. Germline mutation in SUOX gene causes ISOD. Till date, only 32 mutations of SUOX gene have been identified and reported to be associated with ISOD. MethodsHere, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, hyperlactatemia, severe metabolic acidosis, hyperglycemia, and hyperkalemia. ResultsWhole exome sequencing identified a novel homozygous transition (c.1227G > A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. This variant causes partial loss of the dimerization domain of sulfite oxidase. Hence, it is a loss-of-function variant. Proband’s father and mother is carrying this novel variant in a heterozygous state. This variant was not found in 200 ethnically matched normal healthy control individuals. ConclusionsOur study not only expanded the mutational spectrum of SUOX gene associated with ISOD, but also strongly suggested the significance of whole exome sequencing for identifying candidate genes and novel disease-causing variants.

Exome Sequencing Identifies the Extremely Rare ITGAV and FN1 Variants in Early Onset Inflammatory Bowel Disease Patients.

BackgroundMolecular diagnosis of early onset inflammatory bowel disease (IBD) is very important for adopting suitable treatment strategies. Owing to the sparse data available, this study aims to identify the molecular basis of early onset IBD in Arab patients.MethodsA consanguineous Arab family with monozygotic twins presenting early onset IBD was screened by whole exome sequencing (WES). The variants functional characterization was performed by a series of computational biology methods. The IBD variants were further screened in in-house whole exome data of 100 Saudi cohorts ensure their rare prevalence in the population.ResultsGenetic screening has identified the digenic autosomal recessive mode of inheritance of ITGAV (G58V) and FN1 (G313V) variants in IBD twins with early onset IBD. Findings from pathogenicity predictions, stability and molecular dynamics have confirmed the deleterious nature of both variants on structural features of the corresponding proteins. Functional biology data suggested that both genes show abundant expression in gastrointestinal tract and immune organs, involved in immune cell restriction, regulation of different immune related pathways. Data from knockout mouse models for ITGAV gene has revealed that the dysregulated expression of this gene impacts intestinal immune homeostasis. The defective ITGAV and FN1 involved in integrin pathway, are likely to induce intestinal inflammation by disturbing immune homeostasis.ConclusionsOur findings provide novel insights into the molecular etiology of pediatric onset IBD and may likely pave way in developing genomic medicine.

Bi-allelic TTC21A mutations in common variable immunodeficiency patients

Abstract Very little is known about the gene TTC21A – it was first described as a gene in the AP20 sub-region of chr3p.21.3 in which deletions were associated with cancer. Initially, TTC21A mRNA expression was only found in the testis, consistent with a recent study linking homozygous TTC21A mutations to decreased fertility due to structural defects in sperm flagella. Interestingly, the gene is also expressed in B lymphocytes with several smaller predicted protein coding transcripts enriched particularly in naïve and memory B cells. Here we report four individuals of one kindred with common variable immunodeficiency (CVID) with two different sets of rare biallelic TTC21A variants. Based on whole genome sequencing analysis, TTC21A was the only candidate gene that co-segregated with disease across three generations and eight individuals of this family with an autosomal recessive mode of inheritance. The affected individuals had low serum IgG and a significant defect in class-switching. In-depth B cell immunophenotyping revealed that, relative to healthy family controls, the patients had significant skewing of increased transitional (CD27− IgD+ CD24+ CD38+) B cells and markedly reduced terminally differentiated plasmablasts (IgD− CD20low CD38+). The patients with the rare homozygous variant also had significantly reduced expression of the B cell specific TT21A variant relative to the family controls and patients with the compound heterozygous variants. Initial immunization experiments of Ttc21a CRISPR knock-in mice mirrored the patients’ phenotype with decreased class switching; however subsequent repeats have been inconclusive. Additional work is necessary to further elucidate the immune function of TTC21A in B cells. Supported by the NIH Oxford-Cambridge MD/PhD Scholarship

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9); and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8-/- mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60; 80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.

Early onset adult deafness in the Rhodesian Ridgeback dog is associated with an in-frame deletion in the EPS8L2 gene.

Domestic dogs exhibit diverse types of both congenital and non-congenital hearing losses. Rhodesian Ridgebacks can suffer from a progressive hearing loss in the early stage of their life, a condition known as early onset adult deafness (EOAD), where they lose their hearing ability within 1-2 years after birth. In order to investigate the genetic basis of this hereditary hearing disorder, we performed a genome-wide association study (GWAS) by using a sample of 23 affected and 162 control Rhodesian Ridgebacks. We identified a genomic region on canine chromosome 18 (CFA18) that is strongly associated with EOAD, and our subsequent targeted Sanger sequencing analysis identified a 12-bp inframe deletion in EPS8L2 (CFA18:25,868,739-25,868,751 in the UMICH_Zoey_3.1/canFam5 reference genome build). Additional genotyping confirmed a strong association between the 12-bp deletion and EOAD, where all affected dogs were homozygous for the deletion, while none of the control dogs was a deletion homozygote. A segregation pattern of this deletion in a 2-generation nuclear family indicated an autosomal recessive mode of inheritance. Since EPS8L2 plays a critical role in the maintenance and integrity of the inner ear hair cells in humans and other mammals, the inframe deletion found in this study represents a strong candidate causal mutation for EOAD in Rhodesian Ridgebacks. Genetic and clinical similarities between childhood deafness in humans and EOAD in Rhodesian Ridgebacks emphasizes the potential value of this dog breed in translational research in hereditary hearing disorders.

Xeroderma Pigmentosum-Associated Childhood Interstitial Lung Disease.

Chromosomal breakage syndromes are a group of genetic disorders that are ascribable to the autosomal recessive mode of inheritance. Xeroderma pigmentosum is one of the chromosomal breakage syndromes which is due to the involvement of deformity in the deoxyribonucleic acid’s nucleotide excision repair. Xeroderma pigmentosum is a genetic disorder, which is autosomal recessive, heterogeneous, and more common in cases of consanguinity, caused by mutations in at least 10 genes and 9 complementation groups. The disorder is very rare. Patients experience photophobia and extreme photosensitivity and have pigmentary changes in ultraviolet light-exposed areas of the body with freckling, premalignant, and malignant skin lesions arising in keratinocytes soon after the fleeting exposure to sunlight. Patients are also oversensitive to environmental mutagens such as cigarette smoke and possibly to the widely used agricultural insecticide, diazinon. Progressive neurological abnormalities along with some rare complications are also noticed among these patients. Symptoms and thoracic high-resolution computed tomography are considered for diagnosis. Only corticosteroids can be given to limit the progression of the disease. Xeroderma pigmentosum-related interstitial lung disease is one of the rarest forms and we thereby report an interesting case.

Novel bi-allelic MSH4 variants causes meiotic arrest and non-obstructive azoospermia

BackgroundNon-obstructive azoospermia (NOA) is one of the most severe type in male infertility, and the genetic causes of NOA with meiotic arrest remain elusive.MethodsFour Chinese families with NOA participated in the study. We performed whole-exome sequencing (WES) for the four NOA-affected patients in four pedigrees. The candidate causative gene was further verified by Sanger sequencing. Hematoxylin and eosin staining (H&E) and immunohistochemistry (IHC) were carried out to evaluate the stage of spermatogenesis arrested in the patients with NOA.ResultsWe identified two novel homozygous frameshift mutations of MSH4 and two novel compound heterozygous variants in MSH4 in four pedigrees with NOA. Homozygous loss of function (LoF) variants in MSH4 was identified in the NOA-affected patient (P9359) in a consanguineous Chinese family (NM_002440.4: c.805_812del: p.V269Qfs*15) and one patient with NOA (P21504) in another Chinese family (NM_002440.4: c.2220_2223del:p.K741Rfs*2). Also, compound heterozygous variants in MSH4 were identified in two NOA-affected siblings (P9517 and P9517B) (NM_002440.4: c.G1950A: p.W650X and c.2179delG: p.D727Mfs*11), and the patient with NOA (P9540) (NM_002440.4: c.G244A: p.G82S and c.670delT: p.L224Cfs*3). Histological analysis demonstrated lack of spermatozoa in seminiferous tubules of all patients and IHC showed the spermatogenesis arrested at the meiotic prophase I stage. Consistent with the autosomal recessive mode of inheritance, all of these mutations were inherited from heterozygous parental carriers.ConclusionsWe identified that six novel mutations in MSH4 responsible for meiotic arrest and NOA. And these results provide researchers with a new insight to understand the genetic etiology of NOA and to identify new loci for genetic counselling of NOA.

Дифференциально-клинические признаки корнеоретинальной дистрофии Биетти (клинический случай)

Hereditary retinal dystrophies are clinically and genetically heterogeneous group of conditions, many of which have similar symptoms and functional findings, making correct diagnosis difficult. Bietti corneoretinal dystrophy is a rare form of hereditary retinal dystrophy with an autosomal recessive mode of inheritance. With this dystrophy, yellow-white crystals are visualized on the retina and progressive atrophy of the retinal pigment epithelium, pigment accumulation, and sclerosis of the choriocapillaries are observed. A mutation in the CYP4V2 gene leads to the development of the disease. Currently, 50 different CYP4V2 mutations have been described, most of which are missense mutations. The article presents a clinical case of genetically confirmed Bietti corneoretinal dystrophy with a description of the clinical and functional signs that should be considered when making a diagnosis and taken into account in the differential diagnosis of other hereditary retinal dystrophies. Molecular genetic analysis is necessary in doubtful clinical cases, as well as for genetic counseling of relatives at risk and prenatal testing of high-risk pregnancies.

A Late-Preterm Infant with Ichthyosis, Pancytopenia, and Recurrent Sepsis.

A Late-Preterm Infant with Ichthyosis, Pancytopenia, and Recurrent Sepsis.

Case report: Hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders with clinical varieties depending on the genetic profile. Since 1981 it was established the clinical tableau into a pure and a complicated type which among other conditions encompasses mental retardation/cognitive impairments. The genetic profile is as heterogeneous as the clinical one including autosomal dominant, x-linked, and autosomal recessive mode of inheritance. HSP with thin corpus callosum(TCC) is an autosomal recessive form of the disease with a few reported cases in Japan and a limited number of Caucasian patients.

MIA3 Splice Defect in Cane Corso Dogs with Dental-Skeletal-Retinal Anomaly (DSRA).

We investigated a hereditary syndrome in Cane Corso dogs. Affected dogs developed dental-skeletal-retinal anomaly (DSRA), clinically characterized by brittle, discolored, translucent teeth, disproportionate growth and progressive retinal degeneration resulting in vision loss. Combined linkage and homozygosity mapping delineated a 5.8 Mb critical interval. The comparison of whole genome sequence data of an affected dog to 789 control genomes revealed a private homozygous splice region variant in the critical interval. It affected the MIA3 gene encoding the MIA SH3 domain ER export factor 3, which has an essential role in the export of collagen and other secreted proteins. The identified variant, XM_005640835.3:c.3822+3_3822+4del, leads to skipping of two exons from the wild type transcript, XM_005640835.3:r.3712_3822del. Genotypes at the variant were consistent with monogenic autosomal recessive mode of inheritance in a complete family and showed perfect genotype-phenotype association in 18 affected and 22 unaffected Cane Corso dogs. MIA3 variants had previously been shown to cause related phenotypes in humans and mice. Our data in dogs together with the existing functional knowledge of MIA3 variants in other mammalian species suggest the MIA3 splice defect and a near complete loss of gene function as causative molecular pathomechanism for the DSRA phenotype in the investigated dogs.

Multiple variants in XDH and MOCOS underlie xanthine urolithiasis in dogs

Hereditary xanthinuria is a rare autosomal recessive disease caused by missense and loss of function variants in the xanthine dehydrogenase (XDH) or molybdenum cofactor sulfurase (MOCOS) genes. The aim of this study was to uncover variants underlying risk for xanthinuria in dogs. Affected dogs included two Manchester Terriers, three Cavalier King Charles Spaniels, an English Cocker Spaniel, a Dachshund, and a mixed-breed dog. Four putative causal variants were discovered: an XDH c.654G > A splice site variant that results in skipping of exon 8 (mixed-breed dog), a MOCOS c.232G > T splice site variant that results in skipping of exon 2 (Manchester Terriers), a MOCOS p.Leu46Pro missense variant (Dachshund), and a MOCOS p.Ala128Glyfs*30 frameshift variant that results in a premature stop codon (Cavalier King Charles Spaniels and English Cocker Spaniel). The two splice site variants suggest that the regions skipped are critical to the respective enzyme function, though protein misfolding is an alternative theory for loss of function. The MOCOS p.Leu46Pro variant has not been previously reported in human or other animal cases and provides novel data supporting this residue as critical to MOCOS function. All variants were present in the homozygous state in affected dogs, indicating an autosomal recessive mode of inheritance. Allele frequencies of these variants in breed-specific populations ranged from 0 to 0.18. In conclusion, multiple diverse variants appear to be responsible for hereditary xanthinuria in dogs.

Clinical and genetic characteristics of distal arthrogryposis caused by mutations in the PIEZO2 gene

Mutations in the PIEZO2 gene, which is involved in the formation of the mechanosensitive cation channel Piezo2, can cause distal arthrogryposis type 3 (Gordon’s syndrome), type 5, and Marden–Walker syndrome. Clinical and genetic characteristics of two patients with distal arthrogryposis with autosomal dominant inheritance and one with autosomal recessive inheritance are presented. Exome sequencing in one case revealed a de novo mutation in exon 52 of the PIEZO2gene c.8238G>A (p.Trp2746*, NM_022068.3), in the second, a known deletion of three nucleotides in exon 52 of the PIEZO2 gene c.8181_8183delAGA (p Glu2727del, NM_022068.3) was found, in the third, two mutations in the compound heterozygous state – a deletion of four nucleotides leading to a shift in the reading frame in c.1863_1866delTCAG(p.Ser621fs, NM_022068) and a deletion with putative coordinates 10785050–10789339 bp, spanning 15–16 exons of the PIEZO2 gene (NM_022068; LOD 2.40). The third patient was found to have two newly detected mutations in the compound heterozygous state – a deletion of four nucleotides, leading to a shift in the reading frame in exon 14, p.1863_1866delTCAG (p.Ser621fs, NM_022068) and a deletion with assumed coordinates 10785050–10789339 b. o., (NM_022068; LOD 2.40), spanning 15–16 exons of the PIEZO2 gene. The previous assumption was confirmed that heterozygous mutations are more often localized in exon 52 of the PIEZO2 gene and disrupt the amino acid sequence of the C‑terminal region of the protein molecule, while in patients with an autosomal recessive mode of inheritance of the mutation, the N‑terminal region is more often found.

Pathologic characterization of canine multiple system degeneration in the Ibizan hound.

Canine multiple system degeneration (CMSD) is a progressive hereditary neurodegenerative disorder commonly characterized by neuronal degeneration and loss in the cerebellum, olivary nuclei, substantia nigra, and caudate nuclei. In this article, we describe 3 cases of CMSD in Ibizan hounds. All patients exhibited marked cerebellar ataxia and had cerebellar atrophy on magnetic resonance imaging. At necropsy, all cases showed varying degrees of cerebellar atrophy, and 2 cases had gross cavitation of the caudate nuclei. Histologic findings included severe degeneration and loss of all layers of the cerebellum and neuronal loss and degeneration within the olivary nuclei, substantia nigra, and caudate nuclei. Pedigree analysis indicated an autosomal recessive mode of inheritance, but the causative gene in this breed is yet to be identified. CMSD resembles human multiple system atrophy and warrants further investigation.

Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism

The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as “dual molecular diagnosis.” The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.

Issue Information

A Pakistani family with Ehlers–Danlos musculocontractural type 2 disease. (a) Pedigree showing autosomal recessive mode of inheritance for the disease phenotype (b) Protein models with wild and mutated amino acids. (c) (A–E) Distinctive facial features; (F–H) Hands and fingers; (KO) Long toes and bilateral pes cavus feet. Further details can be seen in the article by Ullah et al. in this issue. image

Novel compound heterozygous missense mutations in GDAP1 cause Charcot–Marie–Tooth type 4A

Homozygous or compound heterozygous mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT4A) that are consistent with an autosomal recessive mode of inheritance. The case reported in this study is clinically and genetically diagnosed with recessive CMT4A that is caused by a compound novel heterozygous GDAP1 mutation. The genomic DNA of the proband with the clinical diagnosis of CMT was screened for GDAP1 mutations using a targeted next-generation sequencing (NGS) gene-panel that comprised of 27 CMT genes. Two novel compound heterozygous amino acid changing variants were identified in the GDAP1 gene, c.246C>G p.His82Gln in exon 2 and c.614T>G p.Leu205Trp in exon 5. The two amino acid changing variants were not previously reported in the 1000 Genome, Mutation Taster and gnomAD. Our findings expand the phenotypic characterization of the two novel heterozygous mutations associated with CMT4A (AR-CMT1A) and add to the repertoire of GDAP1 mutations related to autosomal recessive CMT in Chinese populations.

Fetal brain arrest broadens the spectrum of WDR81-related developmental brain malformations.

Fetal brain arrest is an extremely rare genetic disorder that was described in few patients and encompasses very unique findings of underdeveloped cerebral hemispheres in association with collapsed skull bones. Based on the recurrence among sibs, an autosomal recessive mode of inheritance was proposed; however, no causative gene was identified so far. Here, we report the identification of biallelic variants in the WDR81 gene in two unrelated families (4 patients) with fetal brain arrest including the originally described family and an additional new family. Two homozygous variants were identified: a new missense (c.1157T > C, p.Val386Ala) and a previously described frameshift variant, c.4668_4669delAG (p.Gly1557AspfsTer16). We assessed the expression of WDR81 at the protein level by western blot analysis using primary skin fibroblast cultures established from the patient with the missense variant and noticed that WDR81 expression was significantly reduced in comparison to normal control confirming the pathogenicity of this variant. Our findings confirm the involvement of WDR81 in the pathogenesis of fetal brain arrest syndrome and suggest that fetal brain arrest represents the severe end of the spectrum phenotypes caused by pathogenic variants in WDR81. In addition, we reviewed the clinical and molecular data on WDR81-related disorders and phenotype/genotype correlations.

Canine junctional epidermolysis bullosa due to a novel mutation in LAMA3 with severe upper respiratory involvement.

Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone. To characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of puppies with severe upper respiratory involvement, and to identify an associated genetic variant. Five of eight puppies in an Australian cattle dog cross-bred litter showed signs of skin fragility. Three were stillborn and one died at one month of age. The two surviving puppies were presented with blistering skin disease and severe respiratory distress. Additionally, one unaffected sibling was examined and blood was obtained for genetic testing. Post-mortem examination, histopathological evaluation and electron microscopy were performed. Whole genome sequencing (WGS) of one affected puppy was compared to a database of 522 dogs of 55 different breeds for variant analysis. Sanger sequencing of one additional affected and one unaffected sibling confirmed the variant. Clinically, severe mucocutaneous ulcers occurred in frictional areas with claw sloughing. Histopathological results revealed subepidermal clefts and electron microscopy confirmed the split in the lamina lucida. Post-mortem examination documented extensive pharyngeal and laryngeal lesions with granulation tissue and fibrinous exudate obscuring the airway. Moderate tracheal hypoplasia contributed. The WGS revealed a novel missense variant in the laminin α3-chain XP_537297.2p(Asp2867Val), with an autosomal recessive mode of inheritance. A novel variant in LAMA3 caused a generalized and severe phenotype of JEB with an unique clinical presentation of upper airway obstruction.