Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder.

Variants in EFEMP1, encoding Fibulin-3, were previously reported as a rare cause of heritable connective tissue disorder (HCTD) with recurrent hernias and joint hypermobility. We report three new cases with biallelic or monoallelic EFEMP1 variants and severe hernia phenotypes. Two male siblings of 10 and 13 years old presented with marfanoid habitus, recurrent inguinal and umbilical hernias, generalized joint hypermobility, and scoliosis. Parents and halfsiblings reported joint hypermobility and umbilical hernias. The eldest boy died at age 16 from incarcerated gastrointestinal herniation complicated by gastric and bowel necrosis with perforation. Autopsy revealed widespread intestinal diverticula. Immunohistochemistry of skin and fascia tissue did not reveal any abnormalities, including normal staining of elastic fibers. Both siblings harbored compound heterozygous likely pathogenic EFEMP1 variants (c.1320 + 2T > A, p.? and c.698G > A, p.Gly233Asp). An unrelated 58-year-old male had marfanoid features, high myopia, recurrent diaphragmatic and inguinal hernias, and chronic gastrointestinal dilatation with severe malabsorption. Both his dizygotic twin-brother and mother had recurrent hernias and high myopia. This man died at 59 years of age, and autopsy showed extensive diaphragmatic herniation, bowel diverticula, and pulmonary emphysema. A heterozygous EFEMP1 splice-variant (c.81 + 1G > A, p.?) was identified, causing exon skipping leading to a start-loss. Targeted genome reanalysis nor RNA-sequencing revealed a second variant at the other allele. The reported individuals expand the clinical and pathological phenotypes of EFEMP1-related disease, a distinct entity within the spectrum of HCTD. The severe and recurrent hernias, gastrointestinal dilatation, and diverticulosis result in an increased risk for life-threatening complications, demanding early recognition and close monitoring.