Homozygous Nonsense DSP Variants Selectively Affecting Desmoplakin I Cause Carvajal Syndrome in a Consanguineous Arabian Family with Four Affected Female Siblings
A novel homozygous nonsense variant in the transcript 1-specific region of DSP causing Carvajal syndrome is described, characterized by severe biventricular ACM, epidermolytic palmoplantar keratoderma, and woolly hair, in a consanguineous Arabian family with four affected sisters.
Abstract
Introduction: Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by fibrofatty replacement of the myocardium and is associated with heart failure and sudden cardiac death. It can involve either ventricle, including left-dominant forms defined partly by genetic findings. Methods: We investigated a consanguineous family with four affected daughters presenting with ACM, epidermolytic palmoplantar keratoderma, and woolly hair. The two eldest siblings died suddenly during childhood. The remaining two affected siblings underwent genetic analysis using autozygosity mapping and whole-exome sequencing, followed by segregation analysis. Results: Autozygosity mapping identified a shared identity-by-descent (IBD) interval at the DSP locus on chromosome 6. Exome sequencing revealed a novel homozygous nonsense variant (c.4297C>T; p.Gln1433*; rs1554108283) in exon 23 of DSP. This variant introduces a premature termination codon within the region specific to transcript variant 1, sparing transcript variant 2. Both parents were heterozygous carriers. Cardiac imaging in the affected siblings demonstrated biventricular involvement, including left ventricular systolic dysfunction and right ventricular dilatation. Skin biopsy in one patient confirmed epidermolytic palmoplantar keratoderma. Conclusions: We describe a novel homozygous nonsense variant in the transcript 1-specific region of DSP causing Carvajal syndrome, characterized by severe biventricular ACM, epidermolytic palmoplantar keratoderma, and woolly hair, in a consanguineous Arabian family with four affected sisters.
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Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
Short telomere syndromes (STS) are rare telomere biology disorders caused by germline variants affecting telomere maintenance and may present with organ-limited disease (e.g., pulmonary fibrosis) or multisystem involvement. We report a Vietnamese family carrying a heterozygous TERT p. Ala880Thr variant. The proband was a 42-year-old man with cryptogenic cirrhosis who was incidentally found to have a probable usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) and later developed progressive interstitial lung disease (ILD). He also had marked premature graying, platypnea, digital clubbing, and hepatopulmonary syndrome. Cascade evaluation identified two monozygotic twin sisters (41 years) who also had ILD with discrepant severity: one symptomatic with probable UIP and FVC 47% predicted, while the other was asymptomatic with mild probable UIP changes and FVC 84% predicted. Further pedigree assessment identified maternal cryptogenic cirrhosis and two siblings who died in early childhood with transfusion-dependent anemia, suggesting additional hepatic and hematologic manifestations within the family. Panel-based targeted NGS identified the heterozygous TERT p. Ala880Thr variant in the proband and one affected twin sister, and targeted Sanger sequencing confirmed the familial variant in additional relatives. This case series provides detailed clinical and segregation data from a Vietnamese kindred carrying the previously reported TERT p. Ala880Thr variant. It also highlights the need to suspect telomere-related disease when ILD presents at a young age or is accompanied by extrapulmonary features such as cryptogenic liver disease, premature graying, or a suggestive family history. Early genetic testing and cascade counseling may improve recognition and longitudinal surveillance of at-risk relatives.
Nghi Nguyen-Dang, Quoc-Khanh Tran-Le, Khoa Nguyen-Dang et al.· Therapeutic Advances in Resp...· 0 citations
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Bassam Jamalalail, Ahmed A. Khalifa, Bipin Balan et al.· bioRxiv· 0 citations
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes. Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity. Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.
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