Submission Details

ATP6V0A2 was first reported in relation to ATP6V0A2-CDG (also known as autosomal recessive cutis laxa type 2A), an autosomal recessive congenital disorder of glycosylation, in 2008 (Kornak et al, PMID: 18157129). ATP6V0A2-CDG is characterized by the features of cutis laxa (wrinkly, inelastic, droopy skin), typical facial appearance including down-slanting palpebral fissures, generalized connective tissue disorder, abnormalities on brain MRI (typically cortical and cerebellar malformations), and, in some cases, seizures and intellectual disability. Transferrin and ApoCIII glycosylation studies typically show evidence of both type II N- and O-glycosylation defects after 6 months of age; transferrin studies are usually normal before this age (Morava et al, 2009, PMID: 19401719; Van Maldergem et al, 2023, PMID: 20301755).

For the purposes of this curation, Cutis laxa, autosomal recessive, type IIA (MIM# 219200) and Wrinkly skin syndrome (MIM# 278250) were lumped together as ATP6V0A2-related cutis laxa. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern for these two disorders. In fact, per GeneReviews, ATP6V0A2-related cutis laxa “spans a phenotypic spectrum that includes the historical diagnoses of Debré-type cutis laxa (autosomal recessive cutis laxa 2, ARCL2) at the severe end and wrinkly skin syndrome at the mild end; these two phenotypes were thought to be distinct clinical entities until their molecular genetic nature was determined.” (Van Maldergem et al, 2023, PMID: 20301755).

A recent literature review found 65 families with ATP6V0A2-CDG, and 60 distinct variants of which the majority were loss of function (Morlino et al, 2021, PMID: 33369135). Nine variants (5 frameshift, 3 nonsense, 1 splice site) that have been reported in 7 probands in 5 publications are included in this curation (Kornak et al, 2008 PMID: 18157129; Hucthagowder et al, 2009, PMID: 19321599; Ritelli et al, 2014, PMID: 24815019; Al Teneiji et al, 2017, PMID: 28122681; Karacan et al, 2019, PMID: 30474613). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function.

This gene-disease relationship is also supported by experimental evidence (2 points). ATP6V0A2 encodes the a2 subunit of the V0 domain of V-ATPase, and binds phosphoinositide PI(4)P to anchor V-ATPase to the Golgi membrane (Chu et al, 2024, PMID: 38396846). V-ATPases are ATP-dependent proton pumps that maintain organelle luminal pH in eukaryotic cells. These multi-subunit complexes are composed of a V1 domain that hydrolyzes ATP and a V0 domain that translocates protons from the cytosol to the lumen. Disruption of ATP6V0A2 causes abnormal vesicular trafficking, abnormal glycosylation of serum proteins, intracellular accumulation of tropoelastin, and reduced deposition of mature elastin in the extracellular matrix (Hucthagowder et al, 2009, PMID:19321599; Udono et al, 2015, PMID: 26611489). Of note, at least three additional genes encoding subunits of V-ATPase have been reported to be involved in CDG and cutis laxa, ATP6V1E1, ATP6V1A, and ATP6AP1 (Van Damme et al, 2017, PMID: 28065471; Witters et al, 2018, PMID: 29192153).

In summary, there is definitive evidence supporting the relationship between ATP6V0A2 and ATP6V0A2-CDG (autosomal recessive cutis laxa type 2A), an autosomal recessive congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on April 3, 2024 (SOP version 10)