ClinVar Genomic variation as it relates to human health

The copy number loss of 6q16.1q21 involves multiple protein-coding genes, including GRIK2 (OMIM 138244), SIM1 (OMIM 603128), POU3F2 (OMIM 600494), and FBXL2 (OMIM 605654). Among the genes, heterozygous missense variants of GRIK2 are associated with autosomal dominant neurodevelopmental disorder with impaired language and ataxia with or without seizures (NEDLAS) (OMIM 619580). Biallelic loss-of-function variants of GRIK2 are associated with autosomal recessive intellectual developmental disorder-6 (OMIM 611092). Additionally, deletions involving SIM1, as well as other rearrangements disrupting SIM1, have been identified in several individuals with Prader-Willi syndrome-like phenotypes characterized by obesity, hypotonia, and delayed development, as well as other features (Faivre 2002, Holder 2000), and missense variants with impaired function have been identified in other patients with PWS-like features and/or obesity (Bonnefond 2013). Furthermore, deletions involving POU3F2 but not SIM1 have also been identified in individuals with intellectual disability, hypotonia, and obesity, and were found to segregate with the phenotype in multiple families (Kasher 2016). Thus, deletions involving both SIM1 and POU3F2, as well as several other genes falling within the current interval, have been reported in numerous individuals with a consistent PWS-like phenotype, though not always with complete penetrance (Bonaglia 2008, Kasher 2016, Khattabi 2015 Strunk 2016 Wang 2008). Even though hemizygous deletions of individual genes in this interval have not yet been associated with an established clinical phenotype, there is substantial evidence suggesting that deletions in this region contribute to a clinical phenotype. There are no similar copy number losses of this region in the general populations of the Database of Genomic Variants. Thus, based on current medical literature and gene content, this copy number variant (CNV) is interpreted as pathogenic. References: Bonaglia et al., Eur J Hum Genet. 2008 Dec;16(12):1443-9. PMID: 18648397. Bonnefond et al., J Clin Invest. 2013 Jul;123(7):3037-41. PMID: 23778136. Faivre et al., J Med Genet. 2002 Aug;39(8):594-6. PMID: 12161602. Holder et al., Hum Mol Genet. 2000 Jan 1;9(1):101-8. PMID: 10587584. Kasher et al., Am J Hum Genet. 2016 Feb 4;98(2):363-72. PMID: 26833329. Khattabi et al., Eur J Hum Genet. 2015 Aug;23(8):1010-8. PMID: 25351778. Strunk et al., Mol Cytogenet. 2016 Dec 3;9:88. PMID: 27980676. Wang et al., Am J Med Genet A. 2008 Nov 15;146A(22):2975-8. PMID: 18925680.