EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder

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: EFEMP1; haploinsufficiency; hereditary connective tissue disorder; nonsense‐mediated decay.

Figure 1.

a-c) Distinctive craniofacial dysmorphology present in proband and daughter including long triangular face, ptosis, down slanting palpebral fissures, and high-arched palate. d) Mother demonstrates a Beighton maneuver, active forward flexion of the trunk with knees fully extended so that the palms of the hands rest flat on the floor. e) Lateral view of kyphoscoliosis in the proband. f) AP radiograph of proband depicting scoliosis.

Figure 2.

a) Sanger sequencing electropherograms from gDNA samples obtained from cultured fibroblasts confirming the presence of the novel stop-gain variant (red arrow), (NM_001039348.3): c.1084C>T; (p.Arg362*), in the mother and proband and absence in control (only 1 of 2 control samples shown). b) Sanger sequencing electropherograms from cDNA samples obtained from cultured fibroblasts in the presence or absence of the NMD inhibitor CHX. In cDNA obtained from treated cells, the variant allele became detectable at increased levels in both proband and mother, which is seen as an increase in the amplitude of the thymine nucleotide peak.