Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy.

BACKGROUND: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. CASE PRESENTATION: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. CONCLUSIONS: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies.

A Case of HDR Syndrome and Ichthyosis: Dual Diagnosis by Whole-Genome Sequencing of Novel Mutations in GATA3 and STS Genes.

CONTEXT: Atypical presentations of complex multisystem disorders may elude diagnosis based on clinical findings only. Appropriate diagnostic tests may not be available or available tests may not provide appropriate coverage of relevant genomic regions for patients with complex phenotypes. Clinical whole-exome/-genome sequencing is often considered for complex patients lacking a definitive diagnosis. CASE DESCRIPTION: A boy who is now 7 years old presented as a newborn with congenital ichthyosis. At 6 weeks of age, he presented with failure to thrive and hypoparathyroidism. At 4 years of age, he was diagnosed with sensorineural hearing loss. Whole-genome sequencing identified novel mutations in GATA3, which causes HDR syndrome (hypoparathyroidism and deafness), and STS, which causes X -linked congenital ichthyosis. CONCLUSION: Whole-genome sequencing led to a definitive clinical diagnosis in a case where no other clinical test was available for GATA3, and no sequencing panel would have included both genes because they have disparate phenotypes. This case demonstrates the power of whole-genome (or exome) sequencing for patients with complex clinical presentations involving endocrine abnormalities.