ClinVar

Description

The copy number loss of 6q16.1q21 involves multiple protein-coding genes, including GRIK2 (OMIM 138244), SIM1 (OMIM 603128), and POU3F2 (OMIM 600494). Numerous copy number losses within and overlapping the current interval, both de novo and inherited from affected parents, have been reported as 6q16 microdeletions with a Prader-Willi-like phenotype, typically involving obesity, developmental delay/intellectual disability, and sometimes dysmorphic facial features (Izumi 2013, Kasher 2016, Khattabi 2015, Strunk 2016, Wang 2008). GRIK2, SIM1, and POU3F2 have all been suggested to play a role in the phenotypes resulting from deletions within this region. Further, there are no similar copy number losses of this region in the general populations of the Database of Genomic Variants. Based on gene content and review of the medical literature, this copy number variant (CNV) is interpreted as pathogenic. Other information of the 6q16.1q21 deletion: heterozygous missense variants of GRIK2 are associated with autosomal dominant neurodevelopmental disorder with impaired language and ataxia and with or without seizures (OMIM 619580), while biallelic pathogenic variants of GRIK2 are associated with autosomal recessive intellectual developmental disorder-6, which is characterized by developmental delay and cognitive impairment, typically without congenital malformations or facial dysmorphism (OMIM 611092). SIM1 and POU3F2 are not currently associated with OMIM phenotypes. There are also multiple genes in this copy number loss that are associated with autosomal recessive disorders: NDUFAF4 (OMIM 611776), FBXL4 (OMIM 605654), HACE1 (OMIM 610876), POPDC1 (OMIM 604577), and POPDC3 (OMIM 605824). References: Izumi et al., Am J Med Genet A. 2013 Dec;161A(12):3137-43. PMID: 24038875. 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. _x000D__x000D_