Submission Details

GMPPA was first reported in relation to alacrima, achalasia, and intellectual disability syndrome, an autosomal recessive congenital disorder of glycosylation, in 2013 (Koehler et al, PMID: 24035193). To date, about 20 patients have been reported, nearly all with the same triad of symptoms, alacrima, achalasia, and intellectual disability. Other commonly reported findings include dysmorphic features, short stature, ocular symptoms, and hypotonia (Diaz et al, 2020, PMID: 31898852; Oet et al, 2022, PMID: 35607266).The condition has significant phenotypic overlap with Triple-A syndrome, which is caused by biallelic variants in AAAS. However, unlike AAAS, individuals with alacrima, achalasia, and intellectual disability syndrome do not have adrenocortical insufficiency. Eleven variants (including missense, nonsense, frameshift, and canonical splice variants) reported in eleven probands in 2 publications were curated (Koehler et al, 2013, PMID: 24035193; Gold et al, 2017, PMID: 28574218; Diaz et al, 2020, PMID: 31898852). All patients were negative for variants in AAAS. Of note, the majority of patients reported have consanguineous parents and are homozygous. However, compound heterozygous patients have also been reported recently (Geiculescu et al, 2022, PMID: 35665995; Oet et al, 2022, PMID: 35607266). One variant has been identified in two unrelated probands from an indigenous population in Guatemala and may be a founder variant in that population (Diaz et al, 2020, PMID: 31898852). All curated variants are rare or absent in gnomAD v2.1.1. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence including the function of GMPPA, which acts as a negative regular of GMPPB, thereby controlling GDP-mannose levels (Franzka et al, 2021, PMID: 33755596; Franzka et al, 2022, 36672654). Lack of GMPPA has been shown to result in hyperglycosylation of alpha-dystroglcan, and lowered overall alpha-dystroglycan levels, as well as abnormal structure and functionality of the ER and Golgi complex (PMIDs: 33755596, 36672654). Further evidence includes the features observed in a Gmppa knock out mouse (Franzka et al, 2021, PMID: 33755596), and results of siRNA knock down of Gmppa in mouse myoblasts (Franzka et al, 2021, PMID: 33755596). In summary, there is definitive evidence supporting the relationship between GMPPA and alacrima, achalasia, and intellectual disability syndrome, 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 on September 6, 2023 (SOP Version 9).