P458: EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder

Le résumé fourni par la source

Monoallelic gain-of-function mutation in EFEMP1 is known to cause an early-onset isolated retinal dystrophy. Phenotypic spectrum of EFEMP1 was expanded with recent description of four patients with biallelic pathogenic variants in EFEMP1 and features of hereditary connective tissue disorders including facial dysmorphism, loose skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis. We describe the first report of a monoallelic variant in EFEMP1 resulting in comparable phenotypic features of connective tissue disorders in a mother-daughter duo who are heterozygous for a novel stop-gain variant in EFEMP1. A 20-year-old female born with pectus carinatum, bilateral foot deformity, severe hypotonia, and feeding difficulties. At the age of nine she developed scoliosis. She presented at 20 years of age with chronic pain, frequent ankle sprains, easy bruising, and gastroparesis. Her physical exam was remarkable for generalized joint laxity, with Beighton score of 6/9, soft, translucent, and hyperextensible skin, long face with frontal bossing, down-slanting palpebral fissures, bilateral mild ptosis, a high and narrow arched pallet, dental crowding, arachnodactyly, persistent pectus carinatum, and kyphoscoliosis. Genome sequencing on the proband and her mother revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). A complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript and excluded other molecular etiologies for the patients’ phenotype. 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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.