EP11.12: Prenatal diagnosis of a de novo deletion of 3q26.2 involving MECOM in a fetus with multiple congenital anomalies

A non-consanguineous couple presented in the first pregnancy with hygroma colli at the 12 weeks scan. CNV analysis on whole-exome sequencing (WES) data from chorion villi revealed a pathogenic de novo interstitial 2.4 Mbp deletion in 3q26.2, encompassing 4 genes, MECOM (MDS1-EVI1 complex locus) TERC, CLDN11 and SLC7A14. Follow-up ultrasound at 15 weeks showed a large truncus arteriosus, Pierre Robin sequence, absent left kidney and a two-vessel cord. SNV-analysis of the WES data showed no pathogenic single nucleotide variants (SNVs) in genes associated with congenital heart disease (CHD)or Mendelian inherited disorders. Parents decided for termination of pregnancy. External examination confirmed the malformations seen on ultrasound. The constitutional MECOM associated syndrome is known as ‘Radioulnar synostosis with amegakaryocytic thrombocytopenia’ (RUSAT; OMIM 616738) which shows variable severity: bone marrow failure, radioulnar synostosis and brachydactyly/clinodactyly. Most cases are due to SNVs. Our case confirms that MECOM haploinsufficiency due to deletion of the gene leads to a broad clinical phenotype. Although constitutional MECOM deletions are rare, the findings in the fetus are in agreement with previous reports that show CHD in a patient with partial MECOM deletion (PMID 26554871) and variable CHD caused by pathogenic SNV's in the gene (PMID 29540340). Causality is further underlined by animal models showing a pivotal role for MECOM in nephrogenesis and cardiogenesis (PMID 24586749, 24309209, 1893871, 16574097). Although two other deleted genes are associated with autosomal dominant disorders (TERC and CLDN11) no phenotypic features consistent with these disorders were seen. To our knowledge, this is the first prenatal report on a complete MECOM deletion, illustrating the broad and variable clinical features of MECOM haploinsufficiency.