KAT6B – Genitopatellar Syndrome

KAT6B encodes lysine acetyltransferase 6B, a member of the MYST family of histone acetyltransferases crucial for chromatin remodeling and developmental gene regulation. Genitopatellar syndrome (Genitopatellar syndrome, GPS) is a rare autosomal dominant disorder characterized by patellar hypoplasia or aplasia, external genital anomalies, and severe intellectual disability. Heterozygous de novo truncating variants in KAT6B that produce C-terminally truncated proteins without essential acetyltransferase domains underlie GPS pathogenesis.

Initial exome sequencing of five unrelated GPS probands identified four distinct de novo truncating indels and one nonsense variant in the terminal exon of KAT6B, all predicted to escape nonsense-mediated decay and truncate conserved domains (PMID:22265017). Subsequent cohort analyses encompassing over 90 additional patients confirmed clustering of pathogenic variants between exons 17 and 18, correlating with the GPS phenotype rather than Say-Barber-Biesecker-Young-Simpson syndrome (PMID:25424711).

GPS follows an autosomal dominant inheritance pattern, with all reported cases arising from de novo events and no evidence of affected familial segregation. No multigenerational transmission has been documented.

The variant spectrum is dominated by truncating mutations: frameshift and nonsense alleles in the terminal exons disrupt the acidic and transcription activation domains of KAT6B. A representative recurrent variant is c.4592del (p.Asn1531ThrfsTer18) reported in a patient with overlapping GPS and SBBYSS features (PMID:27452416).

Functional studies in patient-derived cells demonstrate reduced histone H3 and H4 acetylation, linking KAT6B truncation to epigenetic dysregulation during development (PMID:22265017). Mouse expression analyses confirm KAT6B’s role in limb, brain, and genital morphogenesis, supporting haploinsufficiency or dominant-negative mechanisms.

Overall, genetic and experimental data establish a definitive relationship between KAT6B and GPS. Clinical sequencing of KAT6B should be prioritized in patients presenting with patellar anomalies and genital tract malformations absent pathogenic FOXL2 variants. KAT6B variant identification enables precise diagnosis, informed genetic counseling, and consideration of epigenetic therapeutic strategies.

Key Take-home: De novo truncating KAT6B variants cause GPS via impaired histone acetylation; KAT6B testing is essential for diagnosis in patellar and genital anomalies.

References

• American Journal of Human Genetics • 2012 • De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. PMID:22265017
• European Journal of Human Genetics • 2015 • Further delineation of the KAT6B molecular and phenotypic spectrum. PMID:25424711
• Clinical Genetics • 2017 • Complex phenotypes blur conventional borders between Say-Barber-Biesecker-Young-Simpson syndrome and genitopatellar syndrome. PMID:27452416

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