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.

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield.

BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

[Myopia, a growing health problem]. / Bijziendheid, een groeiend probleem.

- Myopia is the eye disorder with the most rapid increase in prevalence worldwide. It develops in childhood, with a peak incidence between the ages of 13 to 15 years. - Especially high myopia, i.e. a refractive error of -6 diopters or more, increases the risk of permanent visual impairment during adulthood due to structural abnormalities of the retina and optic nerve.- The cause of myopia is complex. Lifestyle factors in childhood, such as limited time spent outdoors and close work - such as reading and smartphone usage - are risk factors. Furthermore, genetic studies have revealed more than 100 factors associated with the development of myopia. - Pharmacological and optical interventions to inhibit myopia progression are increasingly applied. The use of atropine eye drops in children and has shown to be an effective treatment.