ALG9 – Gillessen-Kaesbach-Nishimura syndrome

Gillessen-Kaesbach-Nishimura syndrome (GIKANIS) is a lethal autosomal recessive congenital disorder of glycosylation characterized by atypical facial features, generalized skeletal dysplasia with mesomelic shortening and round ilia, deficient ossification of cranial and pubic bones, polycystic kidneys, and complex congenital cardiac defects. The disease is caused by biallelic loss-of-function variants in ALG9 leading to impaired N-glycan precursor assembly and multisystem malformations.

Genetic evidence derives from two unrelated cohorts. In a 2016 study of three affected fetuses from two consanguineous families, all individuals were homozygous for the splice-site variant c.1173+2T>A, confirming a founder effect (PMID:25966638). A subsequent report in 2023 described two additional siblings with identical homozygous c.1173+2T>A alleles and concordant prenatal ultrasound findings including polycystic kidneys and unbalanced atrioventricular septal defect (PMID:36326140).

Segregation analysis demonstrated co-segregation of the splice variant with disease in sibling pairs, supporting autosomal recessive inheritance and confirming pathogenicity in three independent pedigrees. In total, five probands across three families have been molecularly characterized with no alternative etiologies identified.

The variant spectrum in GIKANIS is narrow: all reported cases share the homozygous splice-site change c.1173+2T>A, which ablates the donor site of intron 10 and leads to exon 10 skipping and a downstream frameshift truncation of ALG9 (p.Thr??fs). No missense or deep intronic variants have been reported for this phenotype.

Functional studies in patient-derived RNA and mass spectrometry demonstrated complete exon 10 skipping, reduced ALG9 transcript length, and accumulation of monoglycosylated transferrin indicative of CDG-I (PMID:25966638). These findings confirm haploinsufficiency as the mechanism of disease, consistent with loss of α-1,2-mannosyltransferase activity.

The accumulated clinical, genetic, and biochemical evidence supports a Strong ClinGen classification for the ALG9–GIKANIS association. Accurate molecular diagnosis enables prenatal counseling, targeted ultrasound surveillance, and informs reproductive decision-making.

References

• European Journal of Human Genetics • 2016 • A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9. PMID:25966638
• American Journal of Medical Genetics Part A • 2023 • Gillessen-Kaesbach-Nishimura syndrome in two fetuses from Turkey. PMID:36326140

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