ClinVar Genomic variation as it relates to human health

The copy number loss of 2q11.1q11.2 encompasses the 2q11.2 recurrent region, deletions of which have been reported (ClinGen available at https://dosage.clinicalgenome.org/clingen_region.cgi?id=ISCA-37495). Riley et al. reported de novo or familial deletions of this locus in five unrelated patients with variable clinical features, such as hypotonia, developmental delay (DD), intellectual disability (ID), speech delay, attention deficit disorder, and facial dysmorphism (Riley 2015). The authors suggested incomplete penetrance and variable expressivity of their 2q11.2 deletions. Rudd et al also reported a similar deletion at 2q11.2 in an individual with learning disability, ADHD, scoliosis, cafe au lait spots, and additional malformations (Rudd 2009). Although, a large-size case-control study in children with ID/DD, multiple congenital anomalies (MCA), and other developmental phenotypes demonstrated a nominal level of significance in support of enrichment of this deletion in a cased (6/29,085 cases versus 0/19,584 controls, p=0.455; Coe 2014)(ClinGen available at https://dosage.clinicalgenome.org/clingen_region.cgi?id=ISCA-37495). Among the genes involved in this interval, heterozygous loss-of-function sequence variants of TMEM127 have been associated with autosomal dominant susceptibility to pheochromocytoma (OMIM 171300)(also refer to Bausch 2017; Aim 2019), with variable expressivity and reduced penetrance . There are 2 other autosomal dominant genes, STARD7 (OMIM 616712), SNRNP200 (OMIM 601664), however, haploinsufficiency of these 2 genes has not been established. Further, there are no full copy number losses of this region in the general populations of the Database of Genomic Variants. Based on literature review and the characteristics of the gene involved, the clinical significance of this copy number variation (CNV) has been interpreted as likely pathogenic. References: Aim et al. J Med Genet. 2019 Aug;56(8):513-520. PMID: 30877234. Bausch et al. JAMA Oncol. 2017 Sep 1;3(9):1204-1212. PMID: 28384794 Coe et al. Nat Genet. 2014 Oct;46(10):1063-71. PMID: 25217958. Riley et al. Am J Med Genet A. 2015 Nov;167A(11):2664-73. PMID: 26227573. Rudd et al., Hum Mol Genet. 2009 Aug 15;18(16):2957-62. PMID: 19443486