KAT6A – Arboleda-Tham Syndrome

KAT6A encodes a lysine acetyltransferase essential for histone H3 acylation, and heterozygous deleterious variants cause autosomal dominant Arboleda-Tham syndrome (Arboleda-Tham syndrome). First described in 2015, this syndrome is characterized by global developmental delay, intellectual disability, speech impairment, and multisystem involvement including cardiac and gastrointestinal malformations.

Genetic confirmation of the KAT6A–Arboleda-Tham association is based on at least 76 unrelated probands with de novo truncating and missense variants (PMID:30245513) and numerous case reports detailing novel alleles. Most pathogenic alleles are loss-of-function (nonsense, frameshift, splice-site) with a preponderance of late-truncating variants in exons 16–17, correlating with more severe developmental outcomes.

The variant spectrum includes >50 distinct alleles: nonsense (e.g., c.3070C>T (p.Arg1019Ter)) (PMID:36573038), frameshift (c.3048del (p.Leu1017SerfsTer17)) (PMID:38773911), missense (c.3937G>A (p.Asp1313Asn)) (PMID:36386811), and splice-disrupting changes. A rare inherited frameshift variant has been observed in three affected relatives, underscoring variable expressivity and reduced penetrance (PMID:39740728).

Phenotypic hallmarks include intellectual disability, global developmental delay, hypotonia, feeding difficulties, and facial dysmorphism (high arched palate, microcephaly), with congenital heart defects (atrial septal defect) and gastrointestinal anomalies (intestinal malrotation, obstruction) frequently reported. Seizures occur in a minority of patients, and additional features such as cryptorchidism, scoliosis, and immune dysfunction expand the clinical spectrum.

Functional studies demonstrate that KAT6A haploinsufficiency disrupts histone H3K23 acetylation/propionylation, altering chromatin accessibility and gene expression—particularly of posterior HOXC cluster genes—with accompanying neurodevelopmental deficits (PMID:37861717). In patient fibroblasts, pantothenate and L-carnitine supplementation partially restore histone acetylation and bioenergetics, suggesting potential therapeutic avenues (PMID:36553567).

Collectively, the wealth of de novo and inherited cases, consistent genotype-phenotype correlations, and corroborative functional assays fulfill ClinGen criteria for a Definitive gene–disease relationship. Early molecular diagnosis enables timely intervention for cardiac and feeding issues, informs prognosis, and supports genetic counseling.

References

• Genetics in Medicine • 2019 • KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. PMID:30245513
• The Journal of International Medical Research • 2022 • The clinical spectrum of a nonsense mutation in KAT6A: a case report. PMID:36573038
• Frontiers in Genetics • 2022 • Clinical manifestations and genetic analysis of a newborn with Arboleda-Tham syndrome. PMID:36386811
• Human Genetics • 2023 • KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster. PMID:37861717
• Genes • 2022 • Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome. PMID:36553567
• Molecular Genetics & Genomic Medicine • 2024 • Diagnosis of Arboleda-Tham syndrome by whole-exome sequencing in an Asian girl with severe developmental delay. PMID:38773911

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