ClinVar Genomic variation as it relates to human health

The copy number loss of 6q16.1q16.2 involves multiple protein-coding genes, none of which is currently associated with an autosomal dominant disorder. De novo or inherited deletions of 6q16.1q16.2 overlapping this region have been reported in families and unrelated individuals with Prader-Willi-like phenotypes, including developmental delay, intellectual disability, behavioral abnormalities, and susceptibility to obesity and hyperphagia. There are at least two affected individuals with smaller deletions fully encompassed in the current interval, both with neurodevelopmental deficits but not obesity or hyperphagia (Kasher 2016, Strunk 2016, Bonaglia 2008). The proposed regions of overlap in different reports seem to always include the POU3F2 (OMIM 600494) and FBXL4 (OMIM 605654) genes, both of which are contained in this interval. Of note, functional studies have shown that POU3F2 is a critical gene for hypothalamic development and suggested that the neuropsychiatric deficits of patients with 6q16.1q16.2 deletions may be associated with haploinsufficiency of this gene (Kasher 2016). Additionally, there are two genes in this copy number loss that are associated with autosomal recessive disorders: FBXL4 (OMIM 605654) and USP45 (OMIM 618439). There are no similar copy number losses of this region in the general populations of the Database of Genomic Variants. Although hemizygous deletions of this specific locus have not been reported, based on gene content and review of the medical literature, this copy number variant (CNV) is interpreted as likely pathogenic. References: Bonaglia et al., Eur J Hum Genet. 2008 Dec;16(12):1443-9. PMID: 18648397. Kasher et al., Am J Hum Genet. 2016 Feb 4;98(2):363-72. PMID: 26833329. Strunk et al., Mol Cytogenet. 2016 Dec 3;9:88. PMID: 27980676.