ClinVar Genomic variation as it relates to human health

The copy number gain of 16p13.11 involves a few protein-coding genes, including multiple exons of a 3' portion of MYH11 (OMIM 160745), and overlaps a recurrent genomic imbalance. It confers susceptibility to a range of neurodevelopmental disorders including autism spectrum disorder, developmental delay, intellectual disability, and speech delay. Additionally, increased risk for cardiovascular disease has been noted (LA El Khattabi et al., J Med Genet 2020;57(5):301-307, PMID 30287593). The clinical significance of this recurrent duplication has been debated, because similar duplications are repeatedly observed in uncharacterized controls and in unaffected relatives (Ullmann R et al., Hum Mutat. 2007 Jul;28(7):674-82.PMID:17480035; Hannes FD et al., J Med Genet. 2009 Apr;46(4):223-32.PMID: 18550696). However, the duplication is enriched in patients versus controls in multiple case-control studies (Coe et al., Nat Genet.2014 Oct;46(10):1063-71., PMID: 25217958; Girirajan et al., N Engl JMed. 2012 Oct 4;367(14):1321-31., PMID: 22970919), with some exceptions (Kaminsky et al., Genet Med. 2011 Sep;13(9):777-84., PMID:21844811). A male-biased effect on the penetrance of the neurodevelopmental phenotypes has been reported (Tropeano M et al.,PLoS One. 2013 Apr 18;8(4):e61365.; PMID: 23637818). Moreover, Khattabi et al. recently suggest no impact of the size of the duplicated segment on the severity of the phenotype in those patients with 16p13.11 gains (Khattabi et al., J Med Genet. 2020May;57(5):301-307. PMID: 30287593), and proposed NDE1 and miR-484 as candidate genes in the neurocognitive phenotype, both of which are involved in the current gain interval. In addition, heterozygous pathogenic sequence variants (mostly missense) of MYH11 have been associated with autosomal dominant conditions of familial thoracicaortic aneurysm 4 (OMIM 160745) and visceral myopathy 2 (OMIM 619350). Thus, the clinical significance of this CNV is likely pathogenic. Please note: because of variable phenotypic expressivity, incomplete penetrance, and occurrence in control populations, it is best interpreted as a susceptibility locus.