ClinVar Genomic variation as it relates to human health

The copy number loss of 2q32.1q33.1 involves numerous protein-coding genes, including COL3A1 (OMIM 120180) and STAT1 (OMIM 600555), and is expected to cause phenotypic and/or developmental abnormalities. Heterozygous loss-of-function variants of COL3A1, including partial and whole-gene deletions, are associated with autosomal dominant vascular-type Ehlers-Danlos syndrome (OMIM 130050, Meienberg 2010, Legrand 2019, Frank 2015, Ritelli 2020), which is characterized by the major complications of arterial and bowel rupture, uterine rupture during pregnancy, and clinical features of easy bruising, thin skin with visible veins, and characteristic facial features. Additionally, biallelic pathogenic variants of COL3A1 are associated with autosomal recessive polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (OMIM 618343), which is highly variable and characterized by polymicrogyria and other variable structural brain anomalies on imaging, with only some patients showing developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death. Furthermore, heterozygous missense variants of STAT1 are associated with autosomal dominant immunodeficiency type 31A (OMIM 614892), which is characterized by a predisposition to mycobacterial infections. Pathogens reported in IMD31A patients include bacillus Calmette-Guerin (BCG) and Mycobacterium avium complex, as well as Mycobacterium tuberculosis. IMD31A has low penetrance and a mild clinical phenotype with good prognosis for recovery. Heterozygous missense variants of STAT1 are also associated with autosomal dominant immunodeficiency 31C (OMIM 614162), which usually presents in infancy or early childhood with chronic mucocutaneous candidiasis (CMC). Other highly variable features include recurrent bacterial, viral, fungal, and mycoplasmal infections, disseminated dimorphic fungal infections, enteropathy with villous atrophy, and autoimmune disorders, such as hypothyroidism or diabetes mellitus. Additionally, biallelic pathogenic variants of STAT1 are associated with autosomal recessive immunodeficiency 31B (OMIM 613796), which is characterized by susceptibility to mycobacteria, Salmonella, and viruses, with a severe disease course and often fatal outcome. Given the established association of hemizygous deletions of this locus with a clinical phenotype and the absence of similar copy number gains of this region in the general populations of the Database of Genomic Variants, and based on size and gene content, this copy number loss is interpreted as pathogenic. References: Meienberg et al., Eur J Hum Genet. 2010 Dec;18(12):1315-21. PMID: 20648054 Legrand et al., Genet Med. 2019 Jul;21(7):1568-1575. PMID: 30474650 Frank et al., Eur J Hum Genet. 2015 Dec;23(12):1657-64. PMID: 25758994 Ritelli et al., Clin Genet. 2020 Feb;97(2):287-295. PMID: 31600821