Ehlers Danlos syndrome with a likely monogenic cause

Gene: ATP6V1A

Green List (high evidence)

BIALLELIC CASES:
PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).

PMID: 28065471 Van Damme et al., 2017
Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys.
Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum).
All parents reported to be unaffected.

MONOALLELIC CASES:
PMID: 40225911 Ma et al., 2024
Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu).
Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient.

ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).

Created: 9 Sep 2026, 11:03 a.m. | Last Modified: 9 Sep 2026, 12:55 p.m.

Panel Version: 4.17

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cutis laxa, autosomal recessive, type IID, OMIM:617403; autosomal recessive cutis laxa type 2D, MONDO:0027451

Publications

• 28065471
• 33320377
• 40225911

Green List (high evidence)

I don't know

This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: ATP6V1A; Suggested initial gene rating: green

Created: 3 Apr 2019, 3:41 p.m.

Green List (high evidence)

Comment on list classification: changed from Red to Green due to expert review denoting a recent paper that found Mutations in ATP6V1E1 or ATP6V1A caused Autosomal-Recessive Cutis Laxa

Created: 10 Jul 2017, 2:05 p.m.

Green List (high evidence)

Green List (high evidence)

Am J Hum Genet. 2017 Feb 2;100(2):216-227. doi: 10.1016/j.ajhg.2016.12.010. Epub 2017 Jan 5. PMID: 28065471 Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa. Review from EDS National Diagnostic Service North West London Hospital NHS Trust: Dr Angela Brady FRCP PhD, Consultant Clinical Geneticist; Dr Neeti Ghali MBChB MD, Consultant Clinical Geneticist; Dr Fleur S van Dijk MD PhD, Consultant.

Created: 7 Jul 2017, 6:29 p.m.

Green List (high evidence)

3 separate families, though only in one paper so far.

Created: 19 May 2017, 1:50 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cutis laxa, autosomal recessive, type IID

Publications

• PubMed: 28065471