ClinVar

Description

The copy number loss of 10q11.22q11.23 involves several protein-coding genes, including GDF2 (OMIM 605120). Deletions overlapping with the 10q11.2 recurrent region (LCR C-D) have been reported in individuals with developmental delay and intellectual disability, as well as variable other features, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, behavioral anomalies, epilepsy, ataxia, dysphagia, nystagmus, and ptosis. The clinical variability and frequent inheritance of deletions from apparently healthy parents suggest variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and/or nongenetic modifiers (Schwartz 2018, Stankiewicz 2012). The proposed 1.45 Mb smallest region of overlap of approximately 1.5 Mb between LCR-C and LCR-D is encompassed in the current deletion. Additionally, a live born fetus with no anomalies was reported who carried an overlapping 3.4-Mb inherited deletion of 10q11.22q11.23. However, it was unknown whether this individual will develop neurocognitive and/or behavioral abnormalities in the future and there was no follow-up report on that patient. The authors categorized the region as a susceptibility locus (Govaerts 2017). Further, heterozygous missense variants of GDF2 are associated with autosomal dominant hereditary hemorrhagic telangiectasia type 5 (OMIM 615506), and multiple recent studies have proposed an association between GDF2 loss of function variants and autosomal dominant pulmonary arterial hypertension (Zhu 2019, Wang 2019, Eyries 2019, Graf 2018). Thus, based on review of the current literature, this copy number variant (CNV) is interpreted as likely pathogenic. However, an abnormal phenotype is not fully predictable. References: Eyries et al., Eur Respir J. 2019 Mar 14;53(3):1801371. PMID: 30578383. Govaerts et al., Prenat Diagn. 2017 Jan;37(1):73-80. PMID: 27931090. Graf et al., Nat Commun. 2018 Apr 12;9(1):1416. PMID: 29650961. Schwartz et al., Am J Med Genet A. 2018 Jan;176(1):151-155. PMID: 29130637. Stankiewicz et al., Hum Mutat. 2012 Jan;33(1):165-79. PMID: 21948486. Wang et al., Eur Respir J. 2019 Mar 14;53(3):1801609. PMID: 30578397. Zhu et al., Genome Med. 2019 Nov 14;11(1):69. PMID: 31727138.