Biallelic Variants in TRAPPC11 Cause a Neurodevelopmental Disorder with Achalasia and Alacrima

Background/Purpose: Triple A syndrome (achalasia-addisonianism-alacrima syndrome) is primarily associated with pathogenic variants in the AAAS gene. However, some patients presenting with typical clinical features test negative for AAAS variants and remain without a molecular diagnosis. Pathogenic variants in TRAPPC11 have previously been described in limb-girdle muscular dystrophy type 18 (LGMDR18). A recent study identified a novel homozygous TRAPPC11 splice variant in four affected individuals suffering from achalasia, alacrima, as well as neurological and muscular symptoms. Clinical features were reminiscent of triple A syndrome but without affection of the adrenal gland. To describe a novel case of a TRAPPC11-related disorder with features of a “duo-A syndrome” (achalasia and alacrimia without addisonianism), caused by novel compound heterozygous variants, and to compare its clinical and genetic characteristics with previously reported cases.

Methods: Whole-exome sequencing was used to identify the underlying genetic cause in a patient presenting with achalasia, alacrima, optic atrophy, anisocoria, muscular dystrophy, short stature, scoliosis, cerebellar atrophy, dysarthria, and ataxia.

Results: Compound heterozygous variants in TRAPPC11 (c.1114-3C>T and c.1179A>G) were identified in the affected individual. cDNA Analysis revealed skipping of exon 11. This likely results in either a truncated protein or nonsense-mediated mRNA decay.The patient's clinical presentation overlaps with features of the previously reported families. Although no myopathy was detected, the presence of neurological features, such as ataxia and cerebellar atrophy, aligns with characteristics observed in LGMDR18.

Conclusion: These findings further confirm that neurodevelopmental duo-A syndrome represents a novel disease phenotype associated with TRAPPC11 variants.

Publikationsverlauf

Artikel online veröffentlicht:
26. September 2025