ClinVar Genomic variation as it relates to human health

The copy number loss of 11q22.1q22.3 involves multiple protein-coding genes, including CNTN5 (OMIM 607219), TRPC6 (OMIM 603652), YAP1 (OMIM 606608), and MMP13 (OMIM 600108). Deletions of 11q21q22.3 overlapping this region have been reported in individuals with an emerging syndrome characterized by developmental or speech delay, intellectual disability or learning difficulties, facial dysmorphism, hypotonia, short stature, and eye coloboma. Among the reported cases, a 6.5-Mb deletion fully encompassing the current interval was identified in a patient with developmental delay and other unspecified developmental or morphological abnormalities (Kirk 2020). CNTN5, YAP1, and GRI4 were proposed as the most likely candidate genes, two of which are encompassed in the current loss interval. Additionally, there are no similar copy number losses of this region in the general populations of the Database of Genomic Variants. Thus, although hemizygous deletions of this specific locus have not been associated with an established clinical phenotype, based on size and gene content, this copy number loss is interpreted as likely pathogenic. Additional information on the 11q22.1q22.3 segment: Heterozygous sequence variants of YAP1 (missense, nonsense, frameshift) are associated with autosomal dominant ocular coloboma with or without hearing impairment, cleft lip/palate, and/or intellectual disability (OMIM 120433). Additionally, heterozygous sequence variants of TRPC6 are associated with autosomal dominant focal segmental glomerulosclerosis-2 (OMIM 603965). While most TRPC6 pathogenic variants cause a gain-of-function phenotype, other missense variants are reported to cause loss-of function, one of them with a dominant negative effect (Riehle 2016). Further, heterozygous missense variants of MMP13 are associated with autosomal dominant metaphyseal anadysplasia or the Missouri type of spondyloepimetaphyseal dysplasia (OMIM 602111), whereas biallelic variants are associated with autosomal recessive Spahr type metaphyseal dysplasia (OMIM 250400). Lastly, although CNTN5 is not currently associated with an OMIM phenotype, deletions and sequence variants of this gene have been associated with an increased risk for neurodevelopmental disorders, particularly autism spectrum disorders, attention deficit/hyperactivity disorder, and anorexia nervosa (Satterstrom 2020, Oguro-Ando 2017, McRae 2017, Monies 2017). In one large study of autism, patients carrying CNTN5 or CNTN6 (OMIM 607220) copy number or sequence variants were more prone to suffer from hyperacusis (39/48 cases vs. 360/548 controls; P=0.036) and abnormal idiosyncratic-negative response to specific sensory stimuli (23/41 cases vs. 153/505 controls; P=0.001) (Mercati 2017). However, haploinsufficiency has not been established as a disease mechanism for any of the genes in this interval. There are multiple genes in this copy number loss that are associated with autosomal recessive disorders: CFAP300 (OMIM 618058), MMP20 (OMIM 604629), MMP1 (OMIM 120353), and DYNC2H1 (OMIM 603297). References: Kirk et al., Cytogenet Genome Res. 2020;160(4):185-192. PMID: 32316019. McRae et al., Nature. 2017 Feb 23;542(7642):433-438. PMID: 28135719. Mercati et al., Mol Psychiatry. 2017 Apr;22(4):625-633. PMID: 27166760. Monies et al., Hum Genet. 2017 Aug;136(8):921-939. PMID: 28600779. Oguro-Ando et al., Mol Cell Neurosci. 2017 Jan 5. pii: S1044-7431(16)30291-3. PMID: 28064060. Riehle et al., J Am Soc Nephrol. 2016 Sep;27(9):2771-83. PMID: 26892346. Satterstrom et al., Cell. 2020 Feb 6;180(3):568-584.e23. PMID: 31981491.