Autosomal Recessive Cutis Laxa Type IIA (ARCL2A) and Wrinkly Skin Syndrome (WSS) via the ATP6V0A2 Gene

Autosomal recessive cutis laxa type IIA (ARCL2A, also referred as Derby type; OMIM 219200) is characterized by hypotonia, over-folded skin, dysmorphic facial features at birth, development delay, and mental retardation. Other common manifestations include enlarged anterior fontanelle, congenital hip dislocation, high myopia, strabismus, and seizures caused by malformation of cortical and cerebella tissues. The dysmorphic features and abnormal neurological symptoms become severe over time, and some patients may lose the ability to walk by adolescence. However, the skin conditions may improve over time. A few patients have abnormalities in the cardiovascular, urogenital, and hematological systems. Wrinkly skin syndrome (WSS; OMIM 278250) is a relatively mild disorder. Patients with the syndrome may have reduced skin elasticity, dental abnormalities (small teeth, delayed eruption, caries), and delayed closure of the fontanel (Hucthagowder et al. Hum Mol Genet 18:2149–2165, 2009; Morava et al. Eur J Hum Genet 17:1099-1110, 2009; Maldergem et al. Genereview, 2011).

ARCL2A and WSS are inherited in an autosomal recessive manner and are caused by variants in ATP6V0A2, which encodes the a2 subunit of the vesicular H+ pump and is a member of the ATPase protein complex family. Variants in ATP6V0A2 impair Golgi vesicle trafficking and prevent the production of functional glycosylation. This results in reduced or abnormal elastic fiber formation. Most known ATP6V0A2 variants are truncating variants, which were found throughout the gene. Missense variants involving proline residues near or within the transmembrane domain are shown to cause ARCL2A (p.P87L, p.P405L, and p.P792R). In addition, a large in-frame deletion (c.1936_2055del, p.E646_685del) was reported in four unrelated patients originating from Iran and Turkey (Hucthagowder et al. Hum Mol Genet 18(12):2149–2165 2009; Morava et al. Eur J Hum Genet 17:1099-1110, 2009; Maldergem et al. GeneReviews, 2011).

Two studies reported that the ATP6V0A2 variants were identified in 27 out of the 29 clinically-diagnosed ARCL2A or WSS families/patients screened by transferrin isoelectric focusing (Kornak et al. 2008; Hucthagowder et al. 2009).

This test provides full coverage of all coding exons of the ATP6V0A2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.