A novel compound heterozygosity in AAAS gene in two Greek siblings: expanding the genotypic landscape of Allgrove syndrome.

Allgrove syndrome, also known as Triple-A syndrome, is a rare autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenal insufficiency, alongside a broad spectrum of neurological and autonomic dysfunctions. We present a compound heterozygosity for the pathogenic NM_015665.6:c.787T > C, p.(Ser263Pro) and the not previously described in the literature NM_015665.6:c.1442 A > G, p.(His481Arg), as a possible cause for Allgrove syndrome. Exome sequencing was performed in a female patient with achalasia, alacrima, optic atrophy, asymmetrical axonal sensorimotor polyneuropathy, segmental demyelination, and chronic denervation, revealing the above-mentioned compound heterozygosity. Segregation analysis was performed in three siblings of the proband and in the mother. The affected brother of the proband (presenting with achalasia, alacrimia, motor neuropathy, autonomic dysfunction, optic atrophy and osteoporosis), was found to be compound heterozygotes for the same variants. Although the paternal genotype was not available, the absence of the p.(His481Arg) variant in the mother indicates paternal inheritance of this variant, providing indirect evidence that the two AAAS variants are located on different alleles (in trans). The proband and her affected sibling were found to carry compound heterozygosity for the known pathogenic AAAS variant p.(Ser263Pro) and the novel p.(His481Arg) variant. Segregation analysis in available family members supports a contributory role of p.(His481Arg) in the context of autosomal recessive inheritance, however, phase could not be directly confirmed due to the unavailability of the paternal sample. Functional validation and/or identification of the variant in unrelated affected individuals would be required to further clarify its pathogenic significance. We also provide a comprehensive review of reported Allgrove syndrome cases in the literature carrying compound heterozygosity for the NM_015665.6:c.787T > C, p.(Ser263Pro) variant and the respective wide spectrum of this syndrome.