ClinVar Genomic variation as it relates to human health

The 19p13.2p13.12 deletion is expected to cause phenotypic and/or developmental abnormalities. This deletion interval fully encompasses the 19p13.13 deletion syndrome region (OMIM 613638), which is characterized by three core features including overgrowth, ophthalmologic abnormalities such as strabismus and optic nerve atrophy or hypoplasia, and gastrointestinal symptomatology, particularly abdominal pain and vomiting. The defined smallest region of overlap (SRO) encompasses 16 genes involved in diverse processes including MAST1 (612256), NFIX (164005), and CALR (109091). In addition, haploinsufficiency of CACNA1A causes various autosomal dominant progressive and non-progressive cerebellar syndromes and paroxysmal phenotypes, such as developmental and epileptic encephalopathy-42 (OMIM 617106), episodic ataxia type 2 (OMIM 108500), familial hemiplegic migraine-1 with or without progressive cerebellar ataxia (OMIM 141500), and spinocerebellar ataxia-6 (OMIM 183086). Frequently reported comorbidities of CACNA1A-related disorders include psychomotor delay, cognitive impairment, attention deficit/hyperactivity disorder and autism, with the age of onset varying from infancy to adulthood (Damaj et al., Eur J Hum Genet. 2015 Nov;23(11):1505-12. PMID: 25735478; Blumkin et al., J Child Neurol. 2010 Jul;25(7):892-7. PMID: 20097664; Baloh et al., Ann Neurol. 1997 Jan;41(1):8-16. PMID: 9005860). Furter, 19p13.2 deletions overlapping this region, as well as focal deletions and loss-of-function variants of NFIX, are associated with Sotos syndrome-2 (OMIM 614753; also known as Malan syndrome), an overgrowth disorder characterized by tall stature, facial dysmorphism, intellectual disability, and behavioral problems (Bellucco et al., Mol Genet Genomic Med. 2019 Dec;7(12):e997. PMID: 31574590; Priolo et al., Hum Mutat. 2018 Sep;39(9):1226-1237. PMID: 29897170; Malan et al., Am J Hum Genet. 2010 Aug 13;87(2):189-98. PMID: 20673863). Loss of CACNA1A seems to be related to a higher frequency of seizures among individuals with 19p13.2 deletions (Bellucco et al., Mol Genet Genomic Med. 2019 Dec;7(12):e997. PMID: 31574590). There are multiple genes in this copy number loss that are associated with autosomal recessive disorders: MAN2B1 (OMIM 609458), DHPS (OMIM 600944), RNASEH2A (OMIM 606034), GCDH (OMIM 608801), FARSA (OMIM 602918), TRMT1 (OMIM 611669), and CC2D1A (OMIM 610055).