Language
English
Publication Date
1-1-2025
Journal
American Journal of Medical Genetics Part A
DOI
39166428
PMID
39166428
PMCID
PMC11637968
PubMedCentral® Posted Date
1-1-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Fine-Lubinsky syndrome is a rare clinically defined syndrome sometimes referred to as brachycephaly, deafness, cataract, microstomia, and impaired intellectual development syndrome. Here we provide a clinical and molecular update for a sibling pair diagnosed with Fine-Lubinsky syndrome. An extensive genetic work-up, including chromosomal microarray analysis and quad exome sequencing, was nondiagnostic. However, a research reanalysis of their exome sequencing data revealed that both were homozygous for an intronic c.749+39G>A [NM_001383.6] variant in DPH1. RNAseq analysis performed on RNA from fibroblasts revealed significantly reduced expression of DPH1 transcripts suggestive of abnormal splicing followed by nonsense mediated mRNA decay. Since the phenotypes of this sibling pair were consistent with those associated with the inheritance of biallelic pathogenic variants in DPH1, they were given a diagnosis of developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (DEDSSH1). This leads us to recommend that all individuals with a clinical diagnosis of Fine-Lubinsky syndrome be screened for variants in DPH1. The clinical histories of this sibling pair emphasize that hearing loss associated with DEDSSH1 may remit over time and that individuals with DEDSSH1 should be monitored for the development of cardiomyopathy. This case also demonstrates the clinical utility of RNAseq as a means of functionally validating the effects of intronic variants that may affect splicing.
Keywords
Child, Female, Humans, Male, Abnormalities, Multiple, Cataract, Deafness, Developmental Disabilities, Exome Sequencing, Genes, Recessive, Homozygote, Intellectual Disability, Loss of Function Mutation, Pedigree, Phenotype, Siblings, Syndrome, Infant
Published Open-Access
yes
Recommended Citation
Waskow, Emily R; Emrick, Lisa T; Rosenfeld, Jill A; et al., "Recessive Loss-of-Function Variants in DPH1 Identified as the Molecular Cause in a Sibling Pair Previously Diagnosed With Fine-Lubinsky Syndrome" (2025). Faculty, Staff and Students Publications. 5925.
https://digitalcommons.library.tmc.edu/baylor_docs/5925