AHDC1 – Xia-Gibbs Syndrome

Xia-Gibbs syndrome (XGS) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, hypotonia, intellectual disability, obstructive sleep apnea, seizures, and mild dysmorphic facial features. The syndrome is caused by heterozygous de novo mutations in the AT-Hook DNA-binding motif containing 1 (AHDC1; HGNC:25230) gene, leading to a truncated protein and haploinsufficiency. The disease is catalogued as MONDO:0014358 and is also referred to as “AHDC1-related intellectual disability-obstructive sleep apnea-mild dysmorphism syndrome.”

Clinical Validity

Over 270 unrelated individuals have been reported with de novo AHDC1 truncating variants, consistently presenting with core XGS features (PMID:34950897). These variants occur across the single coding exon of AHDC1 and are absent in population databases, supporting a definitive gene–disease relationship. Segregation analysis is limited by the de novo nature of pathogenic alleles and rare mosaic cases; no multi-generation pedigrees have been described.

Genetic Evidence

The inheritance mode is autosomal dominant. Genetic studies have identified at least 50 unique protein-truncating variants (frameshift and nonsense) and several de novo missense variants clustering within conserved AHDC1 domains (PMID:34950897; PMID:33644933). A representative variant is c.2030delG (p.Gly677AlafsTer52) detected by whole-exome sequencing in a Colombian patient (PMID:29230160). No recurrent founder alleles have been observed; most mutations arise de novo.

Functional and Experimental Evidence

Cellular assays of AHDC1 truncations reveal aberrant nuclear and nucleolar localization, indicating disrupted DNA-binding function (PMID:33644933). Luciferase reporter studies demonstrate altered transcriptional activity for rare 5′-UTR and missense variants, implying dosage sensitivity (PMID:31737670). Induced pluripotent stem cell (iPSC) lines and CRISPR/Cas9 zebrafish models with AHDC1 loss-of-function variants recapitulate developmental and neuroanatomical defects, reinforcing a haploinsufficiency mechanism (PMID:37054903).

Conflicting Evidence and Phenotypic Spectrum

Large contiguous deletions including AHDC1 show monoallelic expression compensation in whole-blood studies, suggesting possible regulatory complexity without eliminating pathogenicity of coding variants (PMID:36054313). Phenotypic heterogeneity is noted, with variable features such as craniosynostosis, cardiac anomalies, and overgrowth in some patients, expanding the clinical spectrum beyond classic XGS.

Conclusion

The association between AHDC1 and Xia-Gibbs syndrome is classified as Definitive based on abundant de novo variants in >270 patients, consistent autosomal dominant inheritance, and concordant functional data. Genetic testing for AHDC1 truncating and selected missense variants is clinically useful for diagnosis and management, guiding anticipatory care for neurodevelopmental and sleep-related comorbidities.

Key Take-home: AHDC1 loss-of-function variants cause autosomal dominant Xia-Gibbs syndrome; clinical exome sequencing should include AHDC1 in neurodevelopmental and sleep apnea cohorts.

References

• Molecular syndromology • 2017 • Whole-Exome Sequencing Identifies a de novo AHDC1 Mutation in a Colombian Patient with Xia-Gibbs Syndrome. PMID:29230160
• HGG advances • 2021 • AHDC1 missense mutations in Xia-Gibbs syndrome. PMID:34950897
• Human mutation • 2021 • Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome. PMID:33644933
• BioMed research international • 2019 • Rare Mutations in AHDC1 in Patients with Obstructive Sleep Apnea. PMID:31737670
• Gene • 2023 • Establishment of iPSC lines and zebrafish with loss-of-function AHDC1 variants: Models for Xia-Gibbs syndrome. PMID:37054903

Evidence Based Scoring (AI generated)