| Domain | Key finding / statistic | Evidence type and cohort | Source / date / DOI URL |
|---|---|---|---|
| Disease identity / identifiers | Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), a variant of Ohdo syndrome; OMIM 603736; Orphanet ORPHA:3047; part of the broader KAT6B disorder spectrum with overlap with genitopatellar syndrome (GPS, OMIM 606170) (pqac-00000010, pqac-00000014, pqac-00000016) | Human disease descriptions and cohort review | Zhang et al., *Genetics in Medicine*, 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Shin et al., *J Genet Med*, 2021. https://doi.org/10.5734/JGM.2021.18.2.147 ; Magdalena et al., *Mol Genet Genomic Med*, 2023. https://doi.org/10.1002/mgg3.2265 |
| Synonyms / nomenclature | Also called “SBBYSS,” “SBBYS variant of Ohdo syndrome,” “Say-Barber/Biesecker/Young-Simpson syndrome”; recent literature increasingly uses “KAT6B-related disorders” or “KAT6B spectrum disorders” because GPS/SBBYSS boundaries blur (pqac-00000010, pqac-00000016) | Human reviews and cohort papers | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Magdalena et al., 2023. https://doi.org/10.1002/mgg3.2265 |
| Epidemiology / rarity | Ultra-rare; 2025 review cited 152 molecularly confirmed KAT6B cases globally (86 SBBYSS, 33 GPS, 33 intermediate); prevalence described as <1/million in review text (pqac-00000004, pqac-00000005) | Literature review / compiled human cases | Maglione et al., *Am J Med Genet A*, 2025. https://doi.org/10.1002/ajmg.a.64100 |
| Inheritance | Autosomal dominant; most pathogenic variants are de novo; rare inherited mild familial cases have been reported, including maternal transmission of a splice defect in the Zhang cohort (pqac-00000010, pqac-00000011, pqac-00000014, pqac-00000015) | Human cohort + case reports | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Shin et al., 2021. https://doi.org/10.5734/JGM.2021.18.2.147 ; Davarnia et al., 2024. https://doi.org/10.1186/s13256-023-04237-w |
| Core phenotype | Hallmark SBBYSS features include blepharophimosis/ptosis, mask-like facies, long thumbs/great toes, developmental delay/intellectual disability, hypotonia, feeding problems, patellar anomalies, congenital heart disease, thyroid dysfunction, hearing loss, genital anomalies (pqac-00000012, pqac-00000014, pqac-00000016) | Human case reports and cohort summaries | Lundsgaard et al., *Mol Syndromol*, 2017. https://doi.org/10.1159/000452258 ; Shin et al., 2021. https://doi.org/10.5734/JGM.2021.18.2.147 ; Magdalena et al., 2023. https://doi.org/10.1002/mgg3.2265 |
| Major phenotype frequencies (Zhang 2020 cohort) | Cleft/high-arched palate in 14/32 (44%); patellar anomalies in 8/32 (25%); long thumbs and/or long great toes in 12/15 SBBYSS individuals (80%); other digital anomalies in 12/32 (38%); congenital heart defects in 15/32 (47%) (pqac-00000009) | Human cohort, 32 previously unreported individuals plus literature review | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 |
| Additional phenotype burden (Zhang 2020) | Feeding difficulties / reflux / emesis present in 9 individuals; intestinal malrotation highlighted as a serious but underrecognized complication; genital anomalies frequent, especially in GPS; optic nerve hypoplasia and broader cerebral anomalies more common than initially recognized (pqac-00000009, pqac-00000010, pqac-00000011) | Human cohort review | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 |
| Variant spectrum | Previously published KAT6B spectrum included 56 variants: 22 substitutions, 22 small intragenic deletions, 10 small intragenic duplications, 2 deletion-insertions; Zhang added 24 novel variants including 14 frameshift, 7 nonsense, 1 missense, 2 intronic/splicing; most variants cluster in exon 18 (pqac-00000010, pqac-00000011) | Human molecular cohort / allelic series | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 |
| Genotype–phenotype regions | Variants causing GPS cluster in proximal exon 18, amino acids 1150–1515; in this region, phenotypes were GPS 60%, SBBYSS 19%, intermediate 19%; variants outside this region more often cause SBBYSS/intermediate phenotypes (pqac-00000011) | Human genotype–phenotype analysis | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 |
| Mechanistic model of alleles | More proximal variants may undergo nonsense-mediated decay (NMD) causing haploinsufficiency and milder disease; final/penultimate exon variants may escape NMD and produce truncated proteins with abnormal or dominant-negative effects; this remains partly unvalidated experimentally (pqac-00000008, pqac-00000016) | Human mechanistic inference + translational review | Bergamasco et al., *J Clin Invest*, 2024. https://doi.org/10.1172/JCI167672 ; Magdalena et al., 2023. https://doi.org/10.1002/mgg3.2265 |
| Molecular function / complex biology | KAT6B is a highly conserved MYST-family histone acetyltransferase that regulates gene expression and functions in a multisubunit complex with BRPF1, ING5, and MEAF6; reported histone targets include H3K14, H3K23, and broader H2A/H2B/H3/H4/H1 acetylation in assays (pqac-00000010, pqac-00000013, pqac-00000008) | Review + mechanistic translational study | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Zu et al., *Cancers*, 2022. https://doi.org/10.3390/cancers14174068 ; Bergamasco et al., 2024. https://doi.org/10.1172/JCI167672 |
| 2023 Polish cohort | Six Polish patients with one known and five novel KAT6B variants; all had facial dysmorphism and developmental/speech delay; all but one had hypotonia, ocular anomalies, and long thumbs; knee defects were often milder than classic aplasia/agenesis, supporting broader spectrum classification (pqac-00000016, pqac-00000003) | Human case series, 6 patients | Magdalena et al., *Mol Genet Genomic Med*, 2023. https://doi.org/10.1002/mgg3.2265 |
| 2024 translational advance | In CRISPR-engineered human cells with SBBYSS mutations and Kat6b+/- mice, KAT6B deficiency reduced H3K9 acetylation; mice showed learning, memory, and social deficits; valproic acid and acetyl-L-carnitine increased histone acetylation, partially normalized gene expression, improved sociability, and ALCAR restored learning/memory (pqac-00000008, pqac-00000007) | Human cell lines + mouse model | Bergamasco et al., *J Clin Invest*, 2024. https://doi.org/10.1172/JCI167672 |
| Anatomical / cell-level mechanism | Kat6b is highly expressed in developing brain and adult subventricular zone; deficiency impairs neural stem-cell self-renewal and neuronal differentiation, reduces ventricular-zone proliferation, cortical plate size, cortical layer V pyramidal neurons, and interneurons (pqac-00000008, pqac-00000012, pqac-00000013) | Mouse / review / human case contextualization | Bergamasco et al., 2024. https://doi.org/10.1172/JCI167672 ; Lundsgaard et al., 2017. https://doi.org/10.1159/000452258 ; Zu et al., 2022. https://doi.org/10.3390/cancers14174068 |
| Diagnostics | Molecular diagnosis is typically achieved by NGS/WES or targeted sequencing of KAT6B; chromosomal microarray/karyotype can be normal in affected individuals; if a blepharophimosis syndrome or SBBYSS is suspected, KAT6B sequencing is recommended (pqac-00000012, pqac-00000014) | Human diagnostic case reports | Lundsgaard et al., 2017. https://doi.org/10.1159/000452258 ; Shin et al., 2021. https://doi.org/10.5734/JGM.2021.18.2.147 |
| Surveillance / management | Suggested baseline/routine evaluations include brain MRI and seizure surveillance, ophthalmology, periodic hearing exams, thyroid function testing, echocardiogram, renal ultrasound, and monitoring for contractures/spine anomalies and intestinal malrotation; management is multidisciplinary and symptomatic (pqac-00000011, pqac-00000014, pqac-00000015) | Human cohort recommendations + case management | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Shin et al., 2021. https://doi.org/10.5734/JGM.2021.18.2.147 ; Davarnia et al., 2024. https://doi.org/10.1186/s13256-023-04237-w |
| Prognosis / course | Congenital onset is typical; developmental delay persists; some severe GPS-spectrum cases die in infancy; Zhang reported 3 infant deaths in GPS due to pulmonary hypoplasia/renal disease, prematurity with multiorgan complications, and influenza H1N1 infection (pqac-00000011, pqac-00000014) | Human cohort + neonatal case | Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Shin et al., 2021. https://doi.org/10.5734/JGM.2021.18.2.147 |
| Biomarker / omics development | A 2023 study (not directly readable here) reported DNA methylation episignatures for KAT6A/KAT6B variants; later summaries indicate potential utility for variant interpretation/VUS support, but disease-specific performance metrics should be verified from the primary paper before database use (pqac-00000002, pqac-00000000) | Secondary reporting of omics biomarker work | Maglione et al., 2025 citing 2023 episignature work. https://doi.org/10.1002/ajmg.a.64100 |
| Evidence gaps | No disease-specific approved therapy; no human interventional trial identified for SBBYSS/KAT6B disorders in the current search; prevalence/incidence remain imprecise; penetrance and long-term adult natural history are poorly defined; some mechanistic claims (dominant-negative vs haploinsufficiency by region) remain incompletely validated (pqac-00000008, pqac-00000011, pqac-00000016) | Synthesis of human cohort + translational evidence | Bergamasco et al., 2024. https://doi.org/10.1172/JCI167672 ; Zhang et al., 2020. https://doi.org/10.1038/s41436-020-0811-8 ; Magdalena et al., 2023. https://doi.org/10.1002/mgg3.2265 |


*Table: This table summarizes core evidence for Say-Barber-Biesecker-Young-Simpson syndrome within the KAT6B disorder spectrum, spanning identifiers, inheritance, phenotype frequencies, variant architecture, recent cohorts, translational studies, and current clinical practice gaps.*