Language
English
Publication Date
6-1-2024
Journal
American Journal of Medical Genetics Part A
DOI
10.1002/ajmg.a.63556
PMID
38348595
PMCID
PMC11060917
PubMedCentral® Posted Date
6-1-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.
Keywords
Humans, Haploinsufficiency, Female, Marfan Syndrome, Extracellular Matrix Proteins, Phenotype, Connective Tissue Diseases, Pedigree, Mutation, Nonsense Mediated mRNA Decay, Male, Adult, Alleles, Genetic Predisposition to Disease, Child, EFEMP1, Hereditary connective tissue disorder, Haploinsufficiency, nonsense-mediated decay
Published Open-Access
yes
Recommended Citation
Forghani, Irman; Lang, Steven H; Rodier, Matthew J; et al., "EFEMP1 Haploinsufficiency Causes a Marfan-Like Hereditary Connective Tissue Disorder" (2024). Faculty and Staff Publications. 4337.
https://digitalcommons.library.tmc.edu/baylor_docs/4337