Expanding the phenotype of ATP6AP1 deficiency

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Vacuolar ATPases (V-ATPases) are crucial proton pumps in eukaryotic cells, essential for intracellular compartment acidification.
• The ATP6AP1 gene encodes a V-ATPase accessory subunit, and its pathogenic variants are linked to congenital disorder of glycosylation (CDG).
• ATP6AP1-CDG typically presents with variable symptoms including immunodeficiency, hepatopathy, and neurological issues, though the phenotypic spectrum is evolving.

Purpose of the Study:

• To report and characterize a novel ATP6AP1 gene variant in identical twins presenting with acute liver failure.
• To expand the known phenotypic spectrum of ATP6AP1-related congenital disorder of glycosylation (CDG).
• To re-evaluate the prevalence of neurological versus prenatal and connective tissue manifestations in ATP6AP1-CDG.

Main Methods:

• Clinical presentation and detailed phenotypic analysis of identical twins with acute liver failure.
• Whole-exome sequencing (WES) to identify the genetic cause of the disorder.
• Comparison of the twins' phenotype with previously reported cases of ATP6AP1-CDG.

Main Results:

• Identical twins presented with acute liver failure, jaundice, and distinct prenatal (cystic hygroma, atrial septal defect, ventriculomegaly) and postnatal features (pectus carinatum, connective tissue abnormalities, hypospadias).
• Whole-exome sequencing identified a novel de novo in-frame deletion in the ATP6AP1 gene (c.230_232delACT;p.Tyr77del).
• The twins exhibited significant hepatopathy but lacked neurological sequelae, contrasting with some earlier descriptions of ATP6AP1-CDG.

Conclusions:

• This case expands the phenotypic spectrum of ATP6AP1-CDG, highlighting unique prenatal and postnatal features such as fetal ventriculomegaly and connective tissue abnormalities.
• The absence of neurological symptoms in these twins suggests that neurological manifestations may not be a central feature of all ATP6AP1-CDG cases.
• Prenatal and connective tissue findings may be more common in ATP6AP1-CDG than previously recognized, underscoring the need for comprehensive clinical evaluation and long-term follow-up.