Say-Barber-Biesecker-Young-Simpson Syndrome

Mendelian MONDO:0011365 Pathograph 20 Show in embeddings browser

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; also called the SBBYS variant of Ohdo syndrome; OMIM:603736; MONDO:0011365) is a rare autosomal dominant multiple congenital anomaly / neurodevelopmental disorder caused by heterozygous, almost always de novo, protein-truncating variants in KAT6B, which encodes a MYST-family histone (lysine) acetyltransferase. SBBYSS is defined clinically by an immobile, mask-like facial appearance with severe blepharophimosis and ptosis, long thumbs and long great toes, lacrimal duct anomalies, patellar hypoplasia or dislocation, hypotonia, feeding difficulties, and severe global developmental delay / intellectual disability. Congenital hypothyroidism, dental anomalies, hearing loss, cleft palate, congenital heart defects, and cryptorchidism are frequent additional features. SBBYSS lies at the milder end of the KAT6B-related disorder spectrum and is allelic with genitopatellar syndrome (GPS; OMIM:606170; MONDO:0011640), which is curated separately in this knowledge base.

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Pathophysiology

KAT6B protein-truncating variants (proximal NMD-sensitive and distal last-exon alleles)

SBBYSS is caused by heterozygous, almost always de novo, protein-truncating variants in KAT6B (10q22.2), which encodes a MYST-family histone acetyltransferase. Two distinct allelic classes produce the SBBYSS phenotype: (i) variants distributed throughout the gene proximal to the terminal exon, whose transcripts undergo nonsense-mediated decay and therefore act through haploinsufficiency, and (ii) variants located *distally* within the terminal exon (exon 18), distal to the cluster that causes genitopatellar syndrome, which escape nonsense-mediated decay but are not associated with the gain-of-function activities proposed to explain the GPS-specific features. A recurrent de novo synonymous variant in exon 16 (c.3147G>A, p.(Pro1049Pro)) acts as a splice-site mutation and is a mutational hot spot for SBBYSS. This positional distinction is the molecular basis for the clinical separation of SBBYSS from the allelic, more severe genitopatellar syndrome.

KAT6B hgnc:17582

BRPF1-KAT6B (MOZ/MORF) histone acetyltransferase complex GO:0070776

histone acetyltransferase activity GO:0004402 ↓ DECREASED

nucleus GO:0005634

Downstream

Reduced histone acetylation and transcriptional dysregulation Loss of functional KAT6B protein from truncating alleles reduces the cell's histone acetyltransferase output, lowering histone H3 acetylation.

Show evidence (5 references)

PMID:22077973 SUPPORT Human Clinical

"In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced."

Establishes de novo protein-truncating KAT6B variants as the cause of SBBYSS.

PMID:22715153 SUPPORT Human Clinical

"Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon."

Defines the two allelic classes (NMD-sensitive proximal variants and distal last-exon variants) that produce SBBYSS, distinguishing them from the proximal last-exon GPS cluster.

PMID:22715153 SUPPORT Human Clinical

"We propose that haploinsufficiency or loss of a function mediated by the C-terminal domain causes the common features, whereas gain-of-function activities would explain the features unique to GPS."

Assigns haploinsufficiency / C-terminal loss-of-function to the SBBYSS-and-GPS shared features and reserves the gain-of-function mechanism for GPS-specific features.

+ 2 more references

Reduced histone acetylation and transcriptional dysregulation

KAT6B is a MYST-family histone acetyltransferase that acetylates histone H3 within a tetrameric chromatin-modifying complex with BRPF1, ING5 (or its paralog ING4) and MEAF6, and acts as a transcriptional coactivator. In human cells carrying SBBYSS-specific KAT6B mutations and in Kat6b heterozygous mice, KAT6B deficiency reduces histone H3 lysine 9 acetylation, and CRISPR-engineered KAT6B truncating alleles dysregulate chromatin accessibility and the transcriptome. Loss of KAT6B-dependent acetylation is therefore the proximate molecular lesion linking the KAT6B variant to abnormal developmental and neuronal gene programs; critically, the chromatin lesion is in principle reversible, which is the rationale for acetylation-restoring therapeutic strategies.

internal peptidyl-lysine acetylation (histone H3 acetylation) GO:0018393 ↓ DECREASED chromatin organization GO:0006325 ⚠ ABNORMAL positive regulation of transcription by RNA polymerase II GO:0045944 ↓ DECREASED

chromatin GO:0000785

Downstream

Disrupted craniofacial, limb, skeletal, thyroid and CNS developmental programs Because KAT6B is upregulated during development specifically in the CNS, facial structures and limb buds, the loss of KAT6B-dependent acetylation and the resulting transcriptional dysregulation preferentially derail those developmental programs.

Show evidence (5 references)

PMID:38557491 SUPPORT In Vitro

"Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation."

Human-cell arm of this study, cells carrying SBBYSS-specific KAT6B mutations show reduced histone H3K9 acetylation, the proximate molecular lesion.

PMID:38557491 SUPPORT Model Organism

"Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation."

Mouse arm of the same study, Kat6b heterozygous mice show the same H3K9 acetylation deficit in vivo.

PMID:34519438 PARTIAL In Vitro

"We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways."

Describes the experimental approach used to interrogate chromatin accessibility and the transcriptome downstream of KAT6B truncation; the abstract states the aim but does not itself report which pathways were dysregulated, so this supports the approach rather than the result.

+ 2 more references

Disrupted craniofacial, limb, skeletal, thyroid and CNS developmental programs

KAT6B is upregulated during mammalian development specifically in the developing central nervous system, facial structures, and limb buds, so loss of KAT6B-dependent acetylation preferentially derails those developmental programs. Hypomorphic and null Kat6b mouse models recapitulate the human features: the Qkf hypomorph shows small eyes, ventrally placed ears and long first digits, and germline Kat6b deletion causes premature ossification with shortened craniofacial elements, driven by a shift of mesenchymal progenitors toward an osteoblast-progenitor state with upregulated RUNX2 targets and downregulated SOX9. Convergent dysregulation of these programs produces the multisystem SBBYSS phenotype: the mask-like face with blepharophimosis and ptosis, long thumbs and great toes, patellar and other skeletal anomalies, congenital hypothyroidism, and the neurodevelopmental phenotype.

mesenchymal progenitor cell CL:0000134 osteoblast CL:0000062 neural progenitor cell CL:0011020

skeletal system development GO:0001501 ⚠ ABNORMAL ossification GO:0001503 ⚠ ABNORMAL osteoblast differentiation GO:0001649 ↑ INCREASED nervous system development GO:0007399 ⚠ ABNORMAL eye development GO:0001654 ⚠ ABNORMAL limb development GO:0060173 ⚠ ABNORMAL

Downstream

Mask-like facies Disrupted craniofacial developmental programs produce the immobile, mask-like facial appearance that is the diagnostic gestalt of SBBYSS.

Blepharophimosis Disrupted periocular developmental programs narrow the horizontal palpebral fissures, producing the severe blepharophimosis that is a mandatory diagnostic feature of SBBYSS.

Ptosis Disrupted periocular developmental programs also produce ptosis, which accompanies blepharophimosis in the SBBYSS periocular phenotype.

Long thumbs Dysregulated limb developmental programs produce the long, straight thumbs that are essentially specific to SBBYSS within the KAT6B spectrum and are seen with distal truncating alleles.

Long great toes Dysregulated limb developmental programs likewise produce long great toes (long halluces), the pedal counterpart of the long-thumb phenotype and part of the same serially reused autopod patterning program.

Congenital hypothyroidism KAT6B-dependent transcriptional programs are required for normal thyroid development; their disruption produces congenital hypothyroidism and, in some individuals, thyroid agenesis.

Patellar hypoplasia Disrupted skeletal developmental programs produce patellar anomalies, which in SBBYSS are typically hypoplasia, dysplasia or dislocation rather than the frank aplasia characteristic of genitopatellar syndrome.

Global developmental delay and intellectual disability Disrupted CNS developmental programs and reduced neuronal histone acetylation produce severe global developmental delay and intellectual disability.

Lacrimal duct anomalies Disrupted periocular developmental programs produce lacrimal (tear) duct abnormalities, a feature that distinguishes SBBYSS from GPS.

Congenital heart defects Multisystem developmental dysregulation includes congenital heart malformations, most commonly septal defects.

Hypotonia CNS and neuromuscular developmental dysregulation produces the neonatal and infantile hypotonia that is a core SBBYSS feature.

Feeding difficulties Feeding difficulties in SBBYSS arise downstream of hypotonia and, in some individuals, cleft palate, both of which impair suck and swallow.

Dental anomalies Multisystem developmental dysregulation produces dental anomalies, particularly hypoplastic teeth, which are more frequent in SBBYSS than in genitopatellar syndrome.

Sensorineural hearing loss Multisystem developmental dysregulation produces hearing loss, usually sensorineural, which is more frequent in SBBYSS than in genitopatellar syndrome.

Show evidence (4 references)

PMID:22077973 SUPPORT Model Organism

"During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds."

Developmental expression of KAT6B in CNS, facial structures and limb buds explains why loss of KAT6B function targets exactly the organ systems affected in SBBYSS.

PMID:22077973 SUPPORT Model Organism

"The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype."

A hypomorphic Kat6b mouse recapitulates the ocular, ear and long-first-digit features of SBBYSS, supporting the developmental-program mechanism.

PMID:39832706 SUPPORT Model Organism

"we show that germline deletion of the Kat6b gene in mice causes premature ossification in vivo, resulting in shortened craniofacial elements and increased bone density, as well as shortened tibias with an expanded pre-hypertrophic layer, as compared to wild type controls."

Germline Kat6b deletion produces skeletal and craniofacial developmental abnormalities in vivo, mechanistically linking KAT6B loss to the skeletal and facial phenotypes.

+ 1 more reference

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 1

Congenital heart defects FREQUENT Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:22715153 SUPPORT Human Clinical

"Congenital heart defects are noted in about 50% of subjects with either syndrome, the most frequent defects being atrial septal defects, ventricular septal defects, and a patent foramen ovale."

About 50% frequency maps directly to the FREQUENT (30-79%) band and names the commonest lesions.

PMID:25424711 SUPPORT Human Clinical

"The commonest cardiac anomalies observed in the KAT6B-positive group were atrial and ventricular septal defects and patent ductus arteriosus"

Independently characterises the cardiac lesion spectrum in KAT6B-variant-positive patients.

Digestive 2

Feeding difficulties FREQUENT Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:22715153 SUPPORT Human Clinical

"Feeding difficulties are seen in both conditions. Contributing factors may be hypotonia in both syndromes, laryngomalacia in a minority of GPS subjects and cleft palate in some individuals with SBBYSS."

Documents feeding difficulties in SBBYSS and identifies hypotonia and cleft palate as contributing factors.

PMID:25424711 SUPPORT Human Clinical

"Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients."

Feeding difficulties statistically discriminate KAT6B-variant-positive patients.

Small bowel malrotation VERY_RARE Intestinal malrotation HP:0002566

Show evidence (3 references)

PMID:23236640 SUPPORT Human Clinical

"Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype."

GeneReviews lists small bowel malrotation among the features observed in individuals with either KAT6B phenotype, including SBBYSS.

PMID:25424711 SUPPORT Human Clinical

"An interesting observation was the presence of malrotation of the bowel in two patients with KAT6B sequence variants."

Two of the 57-patient KAT6B cohort had bowel malrotation, supporting the VERY_RARE frequency band.

PMID:32424177 SUPPORT Human Clinical

"Intestinal malrotation and its serious consequences can be present in affected individuals."

A 32-individual KAT6B cohort confirms intestinal malrotation as a clinically consequential feature of the KAT6B disorder spectrum.

Ear 1

Sensorineural hearing loss FREQUENT Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:25424711 SUPPORT Human Clinical

"Hearing loss, often remarked upon in the early literature on SBBS was present in around a third of individuals with likely pathogenic KAT6B variants and was usually sensori-neural in origin."

Around one third of KAT6B-variant individuals had usually sensorineural hearing loss, mapping to the FREQUENT (30-79%) band.

Eye 2

Ptosis VERY_FREQUENT Ptosis HP:0000508

Show evidence (2 references)

PMID:22715153 SUPPORT Human Clinical

"Major criteria: Long thumbs/great toes, immobile mask-like face, blepharophimosis/ptosis, lacrimal duct anomalies, patellar anomalies"

Ptosis is one of the proposed major diagnostic criteria for SBBYSS/KAT6B testing.

PMID:25424711 SUPPORT Human Clinical

"Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."

Ptosis is described as a typical SBBYSS facial feature in a large KAT6B cohort, supporting the VERY_FREQUENT band.

Keratoconus Keratoconus HP:0000563

Show evidence (1 reference)

PMID:34519438 SUPPORT Human Clinical

"we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported."

An expanded KAT6B-spectrum cohort reports keratoconus among newly recognised phenotypes; the source gives no denominator, so no frequency band is assigned.

Genitourinary 1

Cryptorchidism VERY_FREQUENT Cryptorchidism HP:0000028

Show evidence (2 references)

PMID:25424711 SUPPORT Human Clinical

"Genital anomalies, usually cryptorchidism, was universal in males with KAT6B sequence variants and tended to be more severe in GPS, where the genitalia may be ambiguous."

Cryptorchidism was universal in KAT6B-variant males, supporting the VERY_FREQUENT band, with the more severe ambiguous-genitalia end restricted to GPS.

PMID:22715153 SUPPORT Human Clinical

"Cryptorchidism is seen in both conditions but scrotal hypoplasia has only been reported in GPS."

Confirms cryptorchidism in SBBYSS and separates it from GPS-restricted scrotal hypoplasia.

Head and Neck 3

Dental anomalies FREQUENT Abnormality of the dentition HP:0000164

Show evidence (2 references)

PMID:25424711 SUPPORT Human Clinical

"Dental anomalies, particularly hypoplastic teeth, emphasised as a salient feature of SBBS in the early literature, were reported as present in only 21/44 individuals with KAT6B variants though they were a significant distinguishing feature."

21/44 (48%) of KAT6B-variant individuals had dental anomalies, which maps to the FREQUENT (30-79%) band.

PMID:22715153 SUPPORT Human Clinical

"Dental anomalies, thyroid anomalies, and hearing loss are seen in both syndromes, but more frequently in SBBYSS."

Confirms dental anomalies are enriched in SBBYSS relative to GPS.

Cleft palate FREQUENT Cleft palate HP:0000175

Show evidence (2 references)

PMID:25424711 SUPPORT Human Clinical

"Cleft palate was seen in 14/44 patients, drawing attention to the fact that SBBS and GPS deserve consideration as a differential diagnosis for syndromic clefting."

14/44 patients = 32%, which falls in the FREQUENT band (30-79%). Caveat, the denominator mixes SBBS and GPS patients, so the SBBYSS-specific rate is not separately reported and the estimate sits near the FREQUENT/OCCASIONAL boundary.

PMID:22077973 SUPPORT Human Clinical

"A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate."

Independently documents cleft palate in a subset of SBBYSS individuals.

Bulbous nasal tip VERY_FREQUENT Bulbous nose HP:0000414

Show evidence (2 references)

PMID:25424711 SUPPORT Human Clinical

"Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."

The bulbous nasal tip is described as a feature of the "typical" SBBYSS facial gestalt in a 57-patient cohort; "typically" maps to the VERY_FREQUENT band, consistent with the identical mapping applied to blepharophimosis, ptosis and mask-like facies from this same sentence.

PMID:22715153 SUPPORT Human Clinical

"is characterized by blepharophimosis, ptosis, an immobile mask-like face, a bulbous nasal tip, hypotonia, feeding problems, long thumbs and great toes, and dislocated or hypoplastic patellae"

The bulbous nasal tip is part of the canonical SBBYS clinical description.

Immune 1

Recurrent infections Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:34519438 SUPPORT Human Clinical

"we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported."

An expanded KAT6B-spectrum cohort reports recurring infections among newly recognised phenotypes; no denominator is given, so no frequency band is assigned.

Limbs 1

Postaxial polydactyly Postaxial polydactyly HP:0100259

Show evidence (2 references)

PMID:32424177 SUPPORT Human Clinical

"distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported"

Documents polydactyly as a recognised, under-reported distal limb anomaly of the KAT6B disorder spectrum.

ORPHA:3047 PARTIAL Other

"skeletal involvement (polydactyly, long thumb(s) and long first toe(s), and patellar hypoplasia/agenesis)"

Orphanet's structured record for the SBBYS type lists polydactyly among the skeletal involvement, consistent with the KAT6B cohort finding; the record does not specify the postaxial subtype, hence PARTIAL.

Musculoskeletal 2

Hypotonia VERY_FREQUENT Hypotonia HP:0001252

Show evidence (2 references)

PMID:37658610 SUPPORT Human Clinical

"Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes."

Hypotonia is described as a usual presenting feature of SBBYSS.

PMID:25424711 SUPPORT Human Clinical

Hypotonia significantly discriminates KAT6B-variant-positive patients in a 57-patient cohort.

Joint hypermobility FREQUENT Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:37658610 SUPPORT Human Clinical

"Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes."

Joint laxity is listed among the features SBBYSS individuals "usually present with"; "usually" maps to the FREQUENT band under the qualitative-term mapping.

Nervous System 3

Global developmental delay and intellectual disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (2 references)

PMID:25424711 SUPPORT Human Clinical

"All individuals with SBBS, reported so far, have had global developmental delay and severe intellectual disability."

Reports universal global developmental delay and severe intellectual disability across all published SBBYSS individuals, supporting the VERY_FREQUENT band and SEVERE severity.

PMID:22715153 SUPPORT Human Clinical

"Subjects with either syndrome have severe developmental delay and intellectual disability."

Confirms severe developmental delay and intellectual disability in SBBYSS.

Delayed speech and language development VERY_FREQUENT Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:37658610 SUPPORT Human Clinical

"In all of our patients facial dysmorphism as well as developmental and speech delay were present."

All six patients in an SBBYSS cohort had developmental and speech delay, supporting the VERY_FREQUENT band.

Neurobehavioral difficulties Atypical behavior HP:0000708

Show evidence (2 references)

PMID:32424177 SUPPORT Human Clinical

"We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported."

Establishes neurobehavioural difficulties as an under-recognised but recurrent feature of the KAT6B disorder spectrum including SBBYSS.

PMID:38557491 PARTIAL Model Organism

"Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals."

Model-organism corroboration only, the KAT6B-haploinsufficient mouse shows social deficits that the authors describe as mirroring SBBYSS individuals; this supports the mechanistic link but is not human evidence for the phenotype.

Growth 1

Slow growth Growth delay HP:0001510

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype."

GeneReviews lists slow growth among the features observed in individuals with either KAT6B phenotype, including SBBYSS.

Other 11

Blepharophimosis VERY_FREQUENT Blepharophimosis HP:0000581

Show evidence (2 references)

PMID:22077973 SUPPORT Human Clinical

"Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance."

Blepharophimosis is part of the defining clinical description of SBBYSS.

PMID:25424711 SUPPORT Human Clinical

"Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."

A 57-patient KAT6B cohort describes severe blepharophimosis as a typical, near-universal SBBYSS facial feature, supporting the VERY_FREQUENT band.

Mask-like facies VERY_FREQUENT Mask-like facies HP:0000298

Show evidence (2 references)

PMID:22715153 SUPPORT Human Clinical

"Subjects with SBBYSS have a very distinctive facial appearance with a mask-like facies, blepharophimosis and ptosis."

Mask-like facies is described as the very distinctive facial appearance of SBBYSS subjects.

PMID:25424711 SUPPORT Human Clinical

"Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."

The mask-like face is described as typical of SBBYSS in a large cohort, supporting a VERY_FREQUENT band.

Long thumbs VERY_FREQUENT Long thumb HP:0032524

Show evidence (2 references)

PMID:22715153 SUPPORT Human Clinical

"In contrast, subjects with SBBYSS do not have skeletal anomalies but most have long thumbs and great toes, which are not seen in GPS."

Long thumbs are present in most SBBYSS subjects and absent in GPS, establishing the association and its diagnostic value; the VERY_FREQUENT band is carried by the quantitative cohort evidence below rather than by the qualitative "most".

PMID:37658610 SUPPORT Human Clinical

"Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs."

Five of six patients (83%) in an independent SBBYSS cohort had long thumbs, which falls in the VERY_FREQUENT band (80-100%) and is the quantitative basis for that band.

Long great toes VERY_FREQUENT Long hallux HP:0001847

Show evidence (3 references)

PMID:22715153 SUPPORT Human Clinical

"Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."

Long great toes are listed as an SBBYSS-only feature within the KAT6B disorders.

PMID:25424711 SUPPORT Human Clinical

Long great toes statistically discriminate KAT6B-variant-positive from variant-negative patients in a large SBBS/GPS cohort.

PMID:32424177 SUPPORT Human Clinical

"Long thumbs and/or long great toes are often observed in individuals with SBBYSS (in 12/15 (80%) in this cohort)."

12/15 = 80% of clinically classified SBBYSS individuals had long thumbs and/or long great toes, which is the quantitative basis for the VERY_FREQUENT band (80-100%). The measure is reported jointly for thumbs and great toes, so the same figure anchors both digit phenotypes.

Congenital hypothyroidism FREQUENT Congenital hypothyroidism HP:0000851

Show evidence (2 references)

PMID:25424711 SUPPORT Human Clinical

"Thyroid abnormalities were present in 22/42 KAT6B-positive patients where these had been searched for and only 1/22 KAT6B-negative patients, again making this one of the most important distinguishing features. The commonest abnormality was congenital hypothyroidism, with raised TSH."

22/42 (52%) of KAT6B-positive patients had thyroid abnormalities, commonest congenital hypothyroidism, which maps to the FREQUENT (30-79%) band.

PMID:22077973 SUPPORT Human Clinical

"A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate."

Independently documents thyroid abnormalities as a recognised SBBYSS feature.

Patellar hypoplasia Patellar hypoplasia HP:0003065

Show evidence (4 references)

PMID:32424177 SUPPORT Human Clinical

"Patellar anomalies, including agenesis, hypoplasia, delayed ossification and displacement of the patella, were present in 8/32 (25%) of individuals in this cohort."

The only quantitative figure available is 8/32 = 25% in a mixed GPS/SBBYSS cohort, which maps to OCCASIONAL. This conflicts with the qualitative "typically involves" language of the other sources, and patellae are not radiographically assessed in every patient so the figure is likely an underestimate. Because the quantitative and qualitative evidence disagree and the denominator mixes subtypes, no frequency band is assigned rather than guessing.

PMID:37658610 SUPPORT Human Clinical

"This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis."

Patellar hypoplasia/agenesis is described as a typical SBBYSS skeletal problem.

PMID:37658610 SUPPORT Human Clinical

"Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders."

Documents the milder end of the SBBYSS patellar spectrum (dysplasia, dislocation, subluxation) and distinguishes it from severe aplasia.

+ 1 more reference

Lacrimal duct anomalies OCCASIONAL Abnormal lacrimal duct morphology HP:0011481

Show evidence (2 references)

PMID:22715153 SUPPORT Human Clinical

"Several subjects with Ohdo also have lacrimal duct abnormalities."

Lacrimal duct abnormalities are reported in several (a subset of) SBBYSS subjects, consistent with an OCCASIONAL band.

PMID:22715153 SUPPORT Human Clinical

"Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."

Establishes lacrimal duct anomalies as SBBYSS-specific within the KAT6B disorders, supporting their diagnostic value.

Talipes OCCASIONAL Talipes HP:0001883

Show evidence (1 reference)

PMID:25424711 SUPPORT Human Clinical

"In SBBS, the joint contractures were less severe and manifested more frequently as talipes and overlapping fingers and toes"

Identifies talipes as the characteristic SBBYSS form of limb positional anomaly, contrasted with GPS large-joint contractures. The source gives only a comparative statement with no numerator or frequency term, so the OCCASIONAL band is a conservative curator estimate rather than a sourced figure.

Increased fracture susceptibility Increased susceptibility to fractures HP:0002659

Show evidence (1 reference)

PMID:34519438 SUPPORT Human Clinical

"we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported."

An expanded KAT6B-spectrum cohort reports fractures among newly recognised phenotypes; no denominator is given, so no frequency band is assigned.

Cerebral anomalies Abnormal brain morphology HP:0012443

Show evidence (2 references)

PMID:32424177 SUPPORT Human Clinical

Establishes cerebral anomalies as an under-recognised but recurrent feature of the KAT6B disorder spectrum including SBBYSS.

PMID:25424711 PARTIAL Human Clinical

"Several patients with SBBS had either agenesis of the corpus callosum, hydronephrosis and joint contractures, features more typical of GPS."

Documents structural brain involvement specifically in SBBYSS patients, while noting it is more typical of the allelic GPS.

Optic nerve hypoplasia Optic nerve hypoplasia HP:0000609

Show evidence (1 reference)

PMID:32424177 SUPPORT Human Clinical

Establishes optic nerve hypoplasia as an under-recognised but recurrent feature of the KAT6B disorder spectrum including SBBYSS.

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Genetic Associations

KAT6B (CAUSAL)

Gene: KAT6B hgnc:17582 variant_origin: DE_NOVO

Autosomal dominant

Show evidence (5 references)

PMID:22077973 SUPPORT Human Clinical

"Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS."

Identifies KAT6B as the causal gene of SBBYSS with truncating variants clustering in the final exon.

PMID:26334766 SUPPORT Human Clinical

"The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation."

Confirms the exon 18 clustering and near-exclusive protein-truncating nature of SBBYSS alleles.

PMID:26334766 SUPPORT In Vitro

"We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant."

Functional RNA evidence that the recurrent exon 16 synonymous variant acts by creating a cryptic splice acceptor site.

+ 2 more references

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Medical Actions

Multidisciplinary supportive and rehabilitative care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

No disease-modifying therapy exists for SBBYSS. Management is supportive and multidisciplinary, with referral to an early-intervention programme for occupational, physical, speech and feeding therapy beginning in infancy.

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy."

GeneReviews recommends multidisciplinary early-intervention supportive care as the standard of management for KAT6B disorders including SBBYSS.

Thyroid hormone replacement for congenital hypothyroidism

Action: thyroid hormone replacement therapy Ontology label: Hormone Therapy NCIT:C15445

Agent: levothyroxine CHEBI:18332

Congenital hypothyroidism associated with a KAT6B disorder is treated in the standard manner by the appropriate specialist, i.e. with thyroid hormone replacement, and thyroid function requires annual monitoring because hypothyroidism may present or recur after the neonatal period.

Target Phenotypes: Congenital hypothyroidism HP:0000851

Show evidence (2 references)

PMID:23236640 SUPPORT Human Clinical

"abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with KAT6B disorders are treated or managed in the standard manner by the appropriate specialist."

GeneReviews directs that hypothyroidism in KAT6B disorders be treated in the standard manner by the appropriate specialist.

PMID:23236640 SUPPORT Human Clinical

"monitoring for hearing loss, amblyopia, hypothyroidism, and contractures and/or scoliosis should occur annually"

GeneReviews specifies annual surveillance for hypothyroidism, supporting ongoing endocrine management.

Annual multisystem surveillance

Action: clinical surveillance screening Ontology label: Disease Screening NCIT:C15419

Annual surveillance covers developmental progress and educational needs, feeding, and screening for hearing loss, amblyopia, hypothyroidism, and contractures and/or scoliosis. Cardiac and renal function are evaluated and monitored as needed when a malformation is present.

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Evaluations of developmental progress and educational needs, assessment for feeding issues, and monitoring for hearing loss, amblyopia, hypothyroidism, and contractures and/or scoliosis should occur annually."

GeneReviews defines the annual surveillance schedule for KAT6B disorders.

Physical therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physical therapy is used to increase joint mobility, and orthopedic intervention is undertaken as needed for contractures and clubfoot.

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Orthopedic intervention as needed for contractures and clubfoot; physical therapy to increase joint mobility."

GeneReviews recommends physical therapy to improve joint mobility in KAT6B disorders.

Speech and language therapy

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Referral to an early intervention program from infancy is recommended so that speech and language therapy can begin early, addressing the severely delayed or absent speech that is a defining SBBYSS feature.

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy."

GeneReviews recommends early-intervention speech therapy from infancy in KAT6B disorders.

Occupational therapy

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Occupational therapy is delivered through the same early intervention referral and targets the functional consequences of hypotonia, joint laxity and distal limb anomalies on fine motor skills and activities of daily living.

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy."

GeneReviews recommends early-intervention occupational therapy from infancy in KAT6B disorders.

Surgical correction of congenital anomalies

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal or dental anomalies, and lacrimal duct abnormalities, are treated or managed in the standard manner by the appropriate specialist, which for many SBBYSS features means surgical correction (e.g. cleft palate repair, orchidopexy, cardiac repair, lacrimal duct probing).

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal or dental anomalies; abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with KAT6B disorders are treated or managed in the standard manner by the appropriate specialist."

GeneReviews assigns standard specialist (frequently surgical) management to the structural anomalies of KAT6B disorders.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling addresses autosomal dominant, almost always de novo, causation, the resulting low recurrence risk, presumed gonadal mosaicism in a single reported family, and reproductive options. Prenatal and preimplantation genetic testing are possible once the familial variant is known.

Show evidence (1 reference)

PMID:23236640 SUPPORT Human Clinical

"Prenatal and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified."

GeneReviews documents the genetic counseling and prenatal/preimplantation testing options for KAT6B disorders.

Histone-acetylation-restoring therapy (experimental / preclinical)

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

A preclinical proof-of-principle strategy targets the core epigenetic lesion of SBBYSS by restoring histone acetylation. In human cells carrying SBBYSS-specific KAT6B mutations and in Kat6b heterozygous mice, the histone deacetylase inhibitor valproic acid and the acetyl donor acetyl-carnitine (ALCAR) elevated histone acetylation, partially reversed cortical neuronal gene-expression changes, improved sociability, and (for ALCAR) restored learning and memory. This is postnatal, disease-mechanism-directed therapy and is NOT yet clinically validated in humans with SBBYSS.

Mechanism Target:

RESTORES Reduced histone acetylation and transcriptional dysregulation — Valproic acid (an HDAC inhibitor) and acetyl-carnitine (an acetyl donor) act directly on the reduced-histone-acetylation node, raising histone acetylation and partially reversing the downstream transcriptional dysregulation in KAT6B-deficient cells and mice.

Show evidence (1 reference)

PMID:38557491 SUPPORT Model Organism

"Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory."

Confirms that acting on the reduced-acetylation node produces measurable rescue of the downstream neurobehavioural phenotype.

Show evidence (4 references)

PMID:38557491 SUPPORT Model Organism

"Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory."

Preclinical mouse evidence that restoring histone acetylation partially rescues the neurobehavioural phenotype of KAT6B haploinsufficiency.

PMID:38557491 PARTIAL Model Organism

"These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions."

The authors frame the finding as a hypothesis for a subset of SBBYSS individuals, so the evidence is preclinical and not a validated clinical recommendation.

PMID:40083716 PARTIAL Model Organism

"Our results suggest that, in addition to loss-of-function alleles, gain-of-function KAT6B alleles may be detrimental for brain development."

Dosage-sensitivity caveat on this strategy. Because excess KAT6B activity is itself detrimental to brain development, raising KAT6B-dependent acetylation has a two-sided therapeutic window, further limiting the strategy to preclinical status.

+ 1 more reference

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Say-Barber-Biesecker-Young-Simpson Syndrome:

Genitopatellar syndrome MONDO:0011640

Overlapping Features The allelic KAT6B disorder at the severe end of the spectrum (MONDO:0011640), curated separately in this knowledge base. GPS is distinguished from SBBYSS by large-joint flexion contractures, anomalies of the spine, ribs and pelvis, renal cysts and hydronephrosis, and agenesis of the corpus callosum, which are markedly more frequent and more severe in GPS. These are differences of degree rather than absolute discriminators: GeneReviews describes patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips and anomalies of the digits, spine and/or ribs as features of both KAT6B phenotypes, and individual SBBYSS patients with corpus callosum agenesis, hydronephrosis or joint contractures are on record. In SBBYSS the contractures are less severe and present more often as talipes and overlapping digits than as large-joint contractures. Corpus callosum involvement is the nearest thing to a hard discriminator. Long thumbs/great toes and lacrimal duct anomalies, conversely, occur only in SBBYSS. GPS-causing variants sit in the proximal portion of the last exon, SBBYSS-causing variants proximal to the last exon or more distally within it. Overlapping intermediate phenotypes are increasingly recognised under the umbrella "KAT6B spectrum disorders".

Show evidence (4 references)

PMID:22715153 SUPPORT Human Clinical

"Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis, and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."

Enumerates the discriminating features that separate SBBYSS from the allelic genitopatellar syndrome.

PMID:22715153 SUPPORT Human Clinical

"A thin or absent corpus callosum is seen in all subjects with GPS whereas this anomaly has not been observed in SBBYSS."

Corpus callosum involvement is the strongest single discriminator between GPS and SBBYSS in the 2012 series, though later cohorts qualify it (see the PARTIAL item below).

PMID:25424711 PARTIAL Human Clinical

"Several patients with SBBS had either agenesis of the corpus callosum, hydronephrosis and joint contractures, features more typical of GPS."

Qualifies the discriminators, a later and larger cohort found SBBYSS patients with corpus callosum agenesis, hydronephrosis and joint contractures, so these separate the two entities by frequency and severity rather than absolutely.

+ 1 more reference

X-linked Ohdo syndrome (Maat-Kievit-Brunner type)

Overlapping Features A genetically distinct blepharophimosis-intellectual disability syndrome caused by MED12 variants, not KAT6B. It shares blepharophimosis and intellectual disability with SBBYSS but is X-linked and lacks the KAT6B facial gestalt, long thumbs/great toes, patellar anomalies and thyroid involvement. Distinguishing it from SBBYSS is essential because the umbrella term "Ohdo syndrome" spans several genetically separate entities.

Show evidence (1 reference)

PMID:25424711 SUPPORT Human Clinical

"The remaining groups comprised the original patients reported by Ohdo et al,15 The X-linked disorder originally reported by Maat-Kievit et al16 and now known to be due to sequence variants within the MED12 gene,17 and a recessive entity associated with microcephaly and multiple structural anomalies."

Documents that the blepharophimosis-intellectual disability group contains genetically distinct entities including the MED12-related X-linked Ohdo syndrome, which must be separated from KAT6B-related SBBYSS.

🧫

Experimental Models

KMUGMCi008-A patient-derived induced pluripotent stem cell line IPSC_DERIVED_MODEL

A human induced pluripotent stem cell line reprogrammed from peripheral blood mononuclear cells of an individual with the SBBYS variant of Ohdo syndrome carrying a heterozygous KAT6B frameshift variant, generated with Sendai-virus reprogramming. It provides a patient-genotype human cellular system for in vitro disease modelling of SBBYSS, complementing the CRISPR-engineered KAT6B cell lines and the Kat6b mouse models.

Cell source

Patient-derived peripheral blood mononuclear cells

Publication

PMID:39986017

Show evidence (2 references)

PMID:39986017 SUPPORT In Vitro

"The peripheral blood mononuclear cells from a patient carrying heterozygous frameshift mutation of the KAT6B gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit."

Documents the derivation of the patient iPSC line from an SBBYSS individual with a heterozygous KAT6B frameshift variant.

PMID:39986017 SUPPORT In Vitro

"The established human induced pluripotent cell line allow proper in vitro disease modelling of Ohdo syndrome SBBYS variant."

States the intended use of the line as an in vitro disease model of the SBBYS variant of Ohdo syndrome.

{ }

Source YAML

click to show

name: Say-Barber-Biesecker-Young-Simpson Syndrome
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; also called the SBBYS
  variant of Ohdo syndrome; OMIM:603736; MONDO:0011365) is a rare autosomal
  dominant multiple congenital anomaly / neurodevelopmental disorder caused by
  heterozygous, almost always de novo, protein-truncating variants in KAT6B,
  which encodes a MYST-family histone (lysine) acetyltransferase. SBBYSS is
  defined clinically by an immobile, mask-like facial appearance with severe
  blepharophimosis and ptosis, long thumbs and long great toes, lacrimal duct
  anomalies, patellar hypoplasia or dislocation, hypotonia, feeding
  difficulties, and severe global developmental delay / intellectual
  disability. Congenital hypothyroidism, dental anomalies, hearing loss, cleft
  palate, congenital heart defects, and cryptorchidism are frequent additional
  features. SBBYSS lies at the milder end of the KAT6B-related disorder
  spectrum and is allelic with genitopatellar syndrome (GPS; OMIM:606170;
  MONDO:0011640), which is curated separately in this knowledge base.
disease_term:
  preferred_term: Say-Barber-Biesecker-Young-Simpson Syndrome
  term:
    id: MONDO:0011365
    label: blepharophimosis - intellectual disability syndrome, SBBYS type
synonyms:
- SBBYSS
- SBBYS variant of Ohdo syndrome
- Say-Barber-Biesecker variant of Ohdo syndrome
- Young-Simpson syndrome
- Ohdo syndrome, SBBYS variant
- blepharophimosis - intellectual disability syndrome, SBBYS type
references:
- reference: PMID:23236640
  title: "KAT6B Disorders."
  tags:
  - GeneReviews
external_assertions:
- name: Orphanet SBBYS-type blepharophimosis-intellectual disability syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:3047
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=3047
  description: >
    Orphanet's ORPHA:3047 structured record for blepharophimosis-intellectual
    disability syndrome, SBBYS type provides the exact MONDO and OMIM
    cross-references and a clinical definition used to anchor the disease
    identity and core phenotype list in this entry.
  evidence:
  - reference: ORPHA:3047
    reference_title: Blepharophimosis-intellectual disability syndrome, SBBYS type (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0011365 | Exact"
    explanation: Orphanet maps ORPHA:3047 exactly to the MONDO identifier used by this entry.
  - reference: ORPHA:3047
    reference_title: Blepharophimosis-intellectual disability syndrome, SBBYS type (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:603736 | Exact"
    explanation: Orphanet lists OMIM:603736 as an exact external cross-reference, matching the MONDO OMIM xref used for the NEC identity check.
pathophysiology:
- name: KAT6B protein-truncating variants (proximal NMD-sensitive and distal last-exon alleles)
  description: >
    SBBYSS is caused by heterozygous, almost always de novo, protein-truncating
    variants in KAT6B (10q22.2), which encodes a MYST-family histone
    acetyltransferase. Two distinct allelic classes produce the SBBYSS
    phenotype: (i) variants distributed throughout the gene proximal to the
    terminal exon, whose transcripts undergo nonsense-mediated decay and
    therefore act through haploinsufficiency, and (ii) variants located
    *distally* within the terminal exon (exon 18), distal to the cluster that
    causes genitopatellar syndrome, which escape nonsense-mediated decay but
    are not associated with the gain-of-function activities proposed to explain
    the GPS-specific features. A recurrent de novo synonymous variant in exon 16
    (c.3147G>A, p.(Pro1049Pro)) acts as a splice-site mutation and is a
    mutational hot spot for SBBYSS. This positional distinction is the
    molecular basis for the clinical separation of SBBYSS from the allelic,
    more severe genitopatellar syndrome.
  biological_scale: MOLECULAR
  gene:
    preferred_term: KAT6B
    term:
      id: hgnc:17582
      label: KAT6B
  molecular_functions:
  - preferred_term: histone acetyltransferase activity
    term:
      id: GO:0004402
      label: histone acetyltransferase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: nucleus
    term:
      id: GO:0005634
      label: nucleus
  protein_complexes:
  - preferred_term: BRPF1-KAT6B (MOZ/MORF) histone acetyltransferase complex
    term:
      id: GO:0070776
      label: MOZ/MORF histone acetyltransferase complex
  evidence:
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced."
    explanation: Establishes de novo protein-truncating KAT6B variants as the cause of SBBYSS.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon."
    explanation: Defines the two allelic classes (NMD-sensitive proximal variants and distal last-exon variants) that produce SBBYSS, distinguishing them from the proximal last-exon GPS cluster.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that haploinsufficiency or loss of a function mediated by the C-terminal domain causes the common features, whereas gain-of-function activities would explain the features unique to GPS."
    explanation: Assigns haploinsufficiency / C-terminal loss-of-function to the SBBYSS-and-GPS shared features and reserves the gain-of-function mechanism for GPS-specific features.
  - reference: PMID:26334766
    reference_title: "A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome."
    explanation: Documents the recurrent exon 16 synonymous splice-altering allele as an SBBYSS mutational hot spot, expanding the allelic mechanism beyond simple nonsense/frameshift truncation.
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants leading to GPS occur within the proximal portion of exon 18, always between amino acids 1150 and 1515 in this cohort and the literature"
    explanation: Delimits the GPS-associated proximal exon 18 window (amino acids 1150-1515); SBBYSS-causing variants lie outside it, either proximal to the last exon or distal within it, giving the positional basis for the SBBYSS/GPS distinction.
  downstream:
  - target: Reduced histone acetylation and transcriptional dysregulation
    description: >-
      Loss of functional KAT6B protein from truncating alleles reduces the
      cell's histone acetyltransferase output, lowering histone H3 acetylation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38557491
      reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation."
      explanation: Human-cell arm of this study, cells carrying SBBYSS-specific KAT6B mutations show reduced histone H3K9 acetylation, directly linking the SBBYSS lesion to the chromatin defect.
    - reference: PMID:38557491
      reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation."
      explanation: Mouse arm of the same study, Kat6b heterozygous mice independently show the same reduction in histone H3K9 acetylation in vivo.
- name: Reduced histone acetylation and transcriptional dysregulation
  description: >
    KAT6B is a MYST-family histone acetyltransferase that acetylates histone H3
    within a tetrameric chromatin-modifying complex with BRPF1, ING5 (or its
    paralog ING4) and MEAF6, and acts as a transcriptional coactivator. In human cells carrying SBBYSS-specific KAT6B
    mutations and in Kat6b heterozygous mice, KAT6B deficiency reduces histone
    H3 lysine 9 acetylation, and CRISPR-engineered KAT6B truncating alleles
    dysregulate chromatin accessibility and the transcriptome. Loss of
    KAT6B-dependent acetylation is therefore the proximate molecular lesion
    linking the KAT6B variant to abnormal developmental and neuronal gene
    programs; critically, the chromatin lesion is in principle reversible,
    which is the rationale for acetylation-restoring therapeutic strategies.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: internal peptidyl-lysine acetylation (histone H3 acetylation)
    term:
      id: GO:0018393
      label: internal peptidyl-lysine acetylation
    modifier: DECREASED
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  cellular_components:
  - preferred_term: chromatin
    term:
      id: GO:0000785
      label: chromatin
  evidence:
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation."
    explanation: Human-cell arm of this study, cells carrying SBBYSS-specific KAT6B mutations show reduced histone H3K9 acetylation, the proximate molecular lesion.
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation."
    explanation: Mouse arm of the same study, Kat6b heterozygous mice show the same H3K9 acetylation deficit in vivo.
  - reference: PMID:34519438
    reference_title: "Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways."
    explanation: Describes the experimental approach used to interrogate chromatin accessibility and the transcriptome downstream of KAT6B truncation; the abstract states the aim but does not itself report which pathways were dysregulated, so this supports the approach rather than the result.
  - reference: PMID:36077605
    reference_title: "BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It functions in the form of a tetrameric complex with a monocytic leukemia zinc finger protein (MOZ or KAT6A), MOZ-related factor (MORF or KAT6B) or HAT bound to ORC1 (HBO1 or KAT7) and two small non-catalytic proteins, the inhibitor of growth 5 (ING5) or the paralog ING4 and MYST/Esa1-associated factor 6 (MEAF6)."
    explanation: Defines the tetrameric BRPF1-KAT6B-ING5/ING4-MEAF6 complex within which KAT6B exerts its acetyltransferase activity, establishing the molecular context of the SBBYSS lesion.
  - reference: PMID:39537341
    reference_title: "KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particular Sox2, which is a key driver of neural progenitor proliferation, multipotency and brain development."
    explanation: Identifies the specific downstream transcriptional consequence of the H3K9 acetylation deficit - loss of SOX family, especially Sox2, expression in neural stem and progenitor cells.
  downstream:
  - target: Disrupted craniofacial, limb, skeletal, thyroid and CNS developmental programs
    description: >-
      Because KAT6B is upregulated during development specifically in the CNS,
      facial structures and limb buds, the loss of KAT6B-dependent acetylation
      and the resulting transcriptional dysregulation preferentially derail
      those developmental programs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Tissue-restricted developmental expression of KAT6B in CNS, facial structures and limb buds.
    evidence:
    - reference: PMID:22077973
      reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds."
      explanation: The tissue-restricted developmental expression of KAT6B explains why loss of its acetyltransferase output disrupts exactly these developmental programs.
- name: Disrupted craniofacial, limb, skeletal, thyroid and CNS developmental programs
  description: >
    KAT6B is upregulated during mammalian development specifically in the
    developing central nervous system, facial structures, and limb buds, so
    loss of KAT6B-dependent acetylation preferentially derails those
    developmental programs. Hypomorphic and null Kat6b mouse models recapitulate
    the human features: the Qkf hypomorph shows small eyes, ventrally placed
    ears and long first digits, and germline Kat6b deletion causes premature
    ossification with shortened craniofacial elements, driven by a shift of
    mesenchymal progenitors toward an osteoblast-progenitor state with
    upregulated RUNX2 targets and downregulated SOX9. Convergent dysregulation
    of these programs produces the multisystem SBBYSS phenotype: the mask-like
    face with blepharophimosis and ptosis, long thumbs and great toes, patellar
    and other skeletal anomalies, congenital hypothyroidism, and the
    neurodevelopmental phenotype.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: mesenchymal progenitor cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
    modifier: ABNORMAL
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: INCREASED
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  - preferred_term: limb development
    term:
      id: GO:0060173
      label: limb development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds."
    explanation: Developmental expression of KAT6B in CNS, facial structures and limb buds explains why loss of KAT6B function targets exactly the organ systems affected in SBBYSS.
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype."
    explanation: A hypomorphic Kat6b mouse recapitulates the ocular, ear and long-first-digit features of SBBYSS, supporting the developmental-program mechanism.
  - reference: PMID:39832706
    reference_title: "Loss of KAT6B causes premature ossification and promotes osteoblast differentiation during development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that germline deletion of the Kat6b gene in mice causes premature ossification in vivo, resulting in shortened craniofacial elements and increased bone density, as well as shortened tibias with an expanded pre-hypertrophic layer, as compared to wild type controls."
    explanation: Germline Kat6b deletion produces skeletal and craniofacial developmental abnormalities in vivo, mechanistically linking KAT6B loss to the skeletal and facial phenotypes.
  - reference: PMID:39832706
    reference_title: "Loss of KAT6B causes premature ossification and promotes osteoblast differentiation during development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that the loss of KAT6B in mesenchymal progenitor cells promotes transition towards an osteoblast-progenitor state with upregulation of gene targets of RUNX2, a master regulator of osteoblast development and concomitant downregulation of SOX9, a critical gene in chondrocyte development."
    explanation: Identifies the cellular and transcriptional intermediate (mesenchymal progenitor to osteoblast-progenitor shift via RUNX2/SOX9) connecting KAT6B loss to skeletal dysmorphogenesis.
  downstream:
  - target: Mask-like facies
    description: >
      Disrupted craniofacial developmental programs produce the immobile,
      mask-like facial appearance that is the diagnostic gestalt of SBBYSS.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated craniofacial developmental gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subjects with SBBYSS have a very distinctive facial appearance with a mask-like facies, blepharophimosis and ptosis."
      explanation: Links the KAT6B developmental disorder to the characteristic SBBYSS mask-like facial gestalt.
  - target: Blepharophimosis
    description: >
      Disrupted periocular developmental programs narrow the horizontal
      palpebral fissures, producing the severe blepharophimosis that is a
      mandatory diagnostic feature of SBBYSS.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated periocular and eyelid developmental gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subjects with SBBYSS have a very distinctive facial appearance with a mask-like facies, blepharophimosis and ptosis."
      explanation: Links the KAT6B developmental lesion to blepharophimosis in SBBYSS.
  - target: Ptosis
    description: >
      Disrupted periocular developmental programs also produce ptosis, which
      accompanies blepharophimosis in the SBBYSS periocular phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated periocular and levator palpebrae developmental gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subjects with SBBYSS have a very distinctive facial appearance with a mask-like facies, blepharophimosis and ptosis."
      explanation: Links the KAT6B developmental lesion to ptosis in SBBYSS.
  - target: Long thumbs
    description: >
      Dysregulated limb developmental programs produce the long, straight
      thumbs that are essentially specific to SBBYSS within the KAT6B spectrum
      and are seen with distal truncating alleles.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated limb-bud and digit patterning gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In contrast, subjects with SBBYSS do not have skeletal anomalies but most have long thumbs and great toes, which are not seen in GPS. Interestingly, these features are only seen with distal truncations in KAT6B."
      explanation: Establishes long thumbs as an SBBYSS-specific digit phenotype tied to distal KAT6B truncations.
  - target: Long great toes
    description: >
      Dysregulated limb developmental programs likewise produce long great toes
      (long halluces), the pedal counterpart of the long-thumb phenotype and
      part of the same serially reused autopod patterning program.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated limb-bud and digit patterning gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."
      explanation: Establishes long great toes as an SBBYSS-restricted digit phenotype within the KAT6B disorders.
  - target: Congenital hypothyroidism
    description: >
      KAT6B-dependent transcriptional programs are required for normal thyroid
      development; their disruption produces congenital hypothyroidism and, in
      some individuals, thyroid agenesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25424711
      reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thyroid abnormalities were present in 22/42 KAT6B-positive patients where these had been searched for and only 1/22 KAT6B-negative patients, again making this one of the most important distinguishing features. The commonest abnormality was congenital hypothyroidism, with raised TSH."
      explanation: Quantifies thyroid involvement as a KAT6B-variant-dependent phenotype with congenital hypothyroidism as the commonest form.
  - target: Patellar hypoplasia
    description: >
      Disrupted skeletal developmental programs produce patellar anomalies,
      which in SBBYSS are typically hypoplasia, dysplasia or dislocation rather
      than the frank aplasia characteristic of genitopatellar syndrome.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated skeletal patterning and ossification gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patellar anomalies are seen in both conditions, albeit more frequently in GPS."
      explanation: Confirms patellar anomalies as an SBBYSS feature while recording the quantitative difference from GPS.
  - target: Global developmental delay and intellectual disability
    description: >
      Disrupted CNS developmental programs and reduced neuronal histone
      acetylation produce severe global developmental delay and intellectual
      disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced histone H3K9 acetylation in cortical neurons with altered neuronal gene expression.
    - Reduced SOX family (notably Sox2) expression in neural stem and progenitor cells, impairing proliferation, neuronal differentiation and neurite outgrowth.
    evidence:
    - reference: PMID:39537341
      reference_title: "KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth."
      explanation: Establishes the cellular neurodevelopmental defect (impaired progenitor proliferation, differentiation and neurite outgrowth) that links the KAT6B chromatin lesion to the SBBYSS neurodevelopmental phenotype.
    - reference: PMID:10821753
      reference_title: "Querkopf, a MYST family histone acetyltransferase, is required for normal cerebral cortex development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice homozygous for the querkopf mutation have craniofacial abnormalities, fail to thrive in the postnatal period and have defects in central nervous system development."
      explanation: The founding mouse study reports that loss of the Kat6b/Querkopf acetyltransferase produces craniofacial abnormalities, failure to thrive and CNS developmental defects, mirroring the SBBYSS phenotype domains.
    - reference: PMID:10821753
      reference_title: "Querkopf, a MYST family histone acetyltransferase, is required for normal cerebral cortex development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results suggest that Querkopf is an essential component of a genetic cascade regulating cell differentiation in the cortex, probably acting in a multiprotein complex regulating chromatin structure during transcription."
      explanation: Assigns Kat6b/Querkopf a required role in a chromatin-regulating multiprotein complex controlling cortical cell differentiation, the mechanistic route from the chromatin lesion to the neurodevelopmental phenotype.
    - reference: PMID:38557491
      reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals."
      explanation: A KAT6B-haploinsufficient mouse model recapitulates the SBBYSS learning, memory and social phenotype, linking the chromatin lesion to the neurodevelopmental outcome.
  - target: Lacrimal duct anomalies
    description: >
      Disrupted periocular developmental programs produce lacrimal (tear) duct
      abnormalities, a feature that distinguishes SBBYSS from GPS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."
      explanation: Establishes lacrimal duct abnormalities as an SBBYSS-restricted feature within the KAT6B spectrum.
  - target: Congenital heart defects
    description: >
      Multisystem developmental dysregulation includes congenital heart
      malformations, most commonly septal defects.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Congenital heart defects are noted in about 50% of subjects with either syndrome, the most frequent defects being atrial septal defects, ventricular septal defects, and a patent foramen ovale."
      explanation: Quantifies congenital heart defects in the KAT6B disorders including SBBYSS and names the commonest lesions.
  - target: Hypotonia
    description: >
      CNS and neuromuscular developmental dysregulation produces the neonatal
      and infantile hypotonia that is a core SBBYSS feature.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dysregulated CNS and neuromuscular developmental gene expression.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Feeding difficulties are seen in both conditions. Contributing factors may be hypotonia in both syndromes, laryngomalacia in a minority of GPS subjects and cleft palate in some individuals with SBBYSS."
      explanation: Names hypotonia as a manifestation of the KAT6B developmental lesion in SBBYSS.
  - target: Feeding difficulties
    description: >
      Feeding difficulties in SBBYSS arise downstream of hypotonia and, in some
      individuals, cleft palate, both of which impair suck and swallow.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hypotonia and, in some individuals, cleft palate impairing suck and swallow.
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Feeding difficulties are seen in both conditions. Contributing factors may be hypotonia in both syndromes, laryngomalacia in a minority of GPS subjects and cleft palate in some individuals with SBBYSS."
      explanation: Identifies hypotonia and cleft palate as the intermediate contributors to feeding difficulties in SBBYSS.
  - target: Dental anomalies
    description: >
      Multisystem developmental dysregulation produces dental anomalies,
      particularly hypoplastic teeth, which are more frequent in SBBYSS than in
      genitopatellar syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dental anomalies, thyroid anomalies, and hearing loss are seen in both syndromes, but more frequently in SBBYSS."
      explanation: Establishes dental involvement as an SBBYSS-enriched manifestation of the KAT6B developmental lesion.
  - target: Sensorineural hearing loss
    description: >
      Multisystem developmental dysregulation produces hearing loss, usually
      sensorineural, which is more frequent in SBBYSS than in genitopatellar
      syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22715153
      reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dental anomalies, thyroid anomalies, and hearing loss are seen in both syndromes, but more frequently in SBBYSS."
      explanation: Establishes auditory involvement as an SBBYSS-enriched manifestation of the KAT6B developmental lesion.
phenotypes:
- category: Craniofacial
  name: Blepharophimosis
  description: >
    Severe blepharophimosis (narrow horizontal palpebral fissures) is a
    mandatory diagnostic feature of SBBYSS and one of the major criteria that
    should prompt KAT6B testing.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance."
    explanation: Blepharophimosis is part of the defining clinical description of SBBYSS.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."
    explanation: A 57-patient KAT6B cohort describes severe blepharophimosis as a typical, near-universal SBBYSS facial feature, supporting the VERY_FREQUENT band.
- category: Craniofacial
  name: Mask-like facies
  description: >
    An immobile, mask-like facial appearance, reflecting reduced facial
    expressivity, is the diagnostic gestalt of SBBYSS and a major criterion
    for KAT6B testing.
  phenotype_term:
    preferred_term: Mask-like facies
    term:
      id: HP:0000298
      label: Mask-like facies
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects with SBBYSS have a very distinctive facial appearance with a mask-like facies, blepharophimosis and ptosis."
    explanation: Mask-like facies is described as the very distinctive facial appearance of SBBYSS subjects.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."
    explanation: The mask-like face is described as typical of SBBYSS in a large cohort, supporting a VERY_FREQUENT band.
- category: Ophthalmologic
  name: Ptosis
  description: >
    Ptosis accompanies blepharophimosis as part of the SBBYSS periocular
    phenotype and is a major diagnostic criterion; it may be less prominent in
    individuals carrying the recurrent exon 16 synonymous variant.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major criteria: Long thumbs/great toes, immobile mask-like face, blepharophimosis/ptosis, lacrimal duct anomalies, patellar anomalies"
    explanation: Ptosis is one of the proposed major diagnostic criteria for SBBYSS/KAT6B testing.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."
    explanation: Ptosis is described as a typical SBBYSS facial feature in a large KAT6B cohort, supporting the VERY_FREQUENT band.
- category: Skeletal
  name: Long thumbs
  description: >
    Long, straight thumbs are a distinctive and nearly SBBYSS-specific feature
    within the KAT6B spectrum, seen with distal truncating alleles and not in
    classic genitopatellar syndrome.
  phenotype_term:
    preferred_term: Long thumb
    term:
      id: HP:0032524
      label: Long thumb
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, subjects with SBBYSS do not have skeletal anomalies but most have long thumbs and great toes, which are not seen in GPS."
    explanation: Long thumbs are present in most SBBYSS subjects and absent in GPS, establishing the association and its diagnostic value; the VERY_FREQUENT band is carried by the quantitative cohort evidence below rather than by the qualitative "most".
  - reference: PMID:37658610
    reference_title: "Clinical heterogeneity of polish patients with KAT6B-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs."
    explanation: Five of six patients (83%) in an independent SBBYSS cohort had long thumbs, which falls in the VERY_FREQUENT band (80-100%) and is the quantitative basis for that band.
- category: Skeletal
  name: Long great toes
  description: >
    Long great toes (long halluces) accompany long thumbs as an
    SBBYSS-restricted digit phenotype associated with distal KAT6B truncations.
  phenotype_term:
    preferred_term: Long hallux
    term:
      id: HP:0001847
      label: Long hallux
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."
    explanation: Long great toes are listed as an SBBYSS-only feature within the KAT6B disorders.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients."
    explanation: Long great toes statistically discriminate KAT6B-variant-positive from variant-negative patients in a large SBBS/GPS cohort.
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long thumbs and/or long great toes are often observed in individuals with SBBYSS (in 12/15 (80%) in this cohort)."
    explanation: 12/15 = 80% of clinically classified SBBYSS individuals had long thumbs and/or long great toes, which is the quantitative basis for the VERY_FREQUENT band (80-100%). The measure is reported jointly for thumbs and great toes, so the same figure anchors both digit phenotypes.
- category: Neurologic
  name: Global developmental delay and intellectual disability
  description: >
    Severe global developmental delay and intellectual disability are
    essentially universal in SBBYSS, with prominent speech and language delay
    and autism-like behaviours.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  severity: SEVERE
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals with SBBS, reported so far, have had global developmental delay and severe intellectual disability."
    explanation: Reports universal global developmental delay and severe intellectual disability across all published SBBYSS individuals, supporting the VERY_FREQUENT band and SEVERE severity.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects with either syndrome have severe developmental delay and intellectual disability."
    explanation: Confirms severe developmental delay and intellectual disability in SBBYSS.
- category: Neurologic
  name: Delayed speech and language development
  description: >
    Speech and language development is disproportionately affected in SBBYSS
    and was present in every patient of an independent SBBYSS cohort.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37658610
    reference_title: "Clinical heterogeneity of polish patients with KAT6B-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all of our patients facial dysmorphism as well as developmental and speech delay were present."
    explanation: All six patients in an SBBYSS cohort had developmental and speech delay, supporting the VERY_FREQUENT band.
- category: Neurologic
  name: Hypotonia
  description: >
    Hypotonia is a core SBBYSS feature, contributes to feeding difficulties and
    delayed motor milestones, and is one of the features that statistically
    predicts a pathogenic KAT6B variant.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37658610
    reference_title: "Clinical heterogeneity of polish patients with KAT6B-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes."
    explanation: Hypotonia is described as a usual presenting feature of SBBYSS.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients."
    explanation: Hypotonia significantly discriminates KAT6B-variant-positive patients in a 57-patient cohort.
- category: Endocrine
  name: Congenital hypothyroidism
  description: >
    Congenital hypothyroidism with raised TSH is the commonest thyroid
    abnormality in SBBYSS; thyroid agenesis is also documented. Thyroid
    involvement is one of the strongest discriminators of a pathogenic KAT6B
    variant and requires lifelong surveillance.
  phenotype_term:
    preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thyroid abnormalities were present in 22/42 KAT6B-positive patients where these had been searched for and only 1/22 KAT6B-negative patients, again making this one of the most important distinguishing features. The commonest abnormality was congenital hypothyroidism, with raised TSH."
    explanation: 22/42 (52%) of KAT6B-positive patients had thyroid abnormalities, commonest congenital hypothyroidism, which maps to the FREQUENT (30-79%) band.
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate."
    explanation: Independently documents thyroid abnormalities as a recognised SBBYSS feature.
- category: Skeletal
  name: Patellar hypoplasia
  description: >
    Patellar anomalies in SBBYSS are typically hypoplasia, dysplasia,
    subluxation or habitual dislocation, and are generally milder than the
    frank patellar aplasia/agenesis that characterises the allelic
    genitopatellar syndrome.
  phenotype_term:
    preferred_term: Patellar hypoplasia
    term:
      id: HP:0003065
      label: Patellar hypoplasia
  evidence:
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patellar anomalies, including agenesis, hypoplasia, delayed ossification and displacement of the patella, were present in 8/32 (25%) of individuals in this cohort."
    explanation: The only quantitative figure available is 8/32 = 25% in a mixed GPS/SBBYSS cohort, which maps to OCCASIONAL. This conflicts with the qualitative "typically involves" language of the other sources, and patellae are not radiographically assessed in every patient so the figure is likely an underestimate. Because the quantitative and qualitative evidence disagree and the denominator mixes subtypes, no frequency band is assigned rather than guessing.
  - reference: PMID:37658610
    reference_title: "Clinical heterogeneity of polish patients with KAT6B-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis."
    explanation: Patellar hypoplasia/agenesis is described as a typical SBBYSS skeletal problem.
  - reference: PMID:37658610
    reference_title: "Clinical heterogeneity of polish patients with KAT6B-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders."
    explanation: Documents the milder end of the SBBYSS patellar spectrum (dysplasia, dislocation, subluxation) and distinguishes it from severe aplasia.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patellar anomalies are seen in both conditions, albeit more frequently in GPS."
    explanation: Confirms patellar anomalies occur in SBBYSS but less frequently than in GPS, consistent with the FREQUENT rather than VERY_FREQUENT band.
- category: Ophthalmologic
  name: Lacrimal duct anomalies
  description: >
    Tear (lacrimal) duct abnormalities, including obstruction, are a
    distinguishing SBBYSS feature not seen in classic genitopatellar syndrome,
    and are a major criterion prompting KAT6B testing.
  phenotype_term:
    preferred_term: Abnormal lacrimal duct morphology
    term:
      id: HP:0011481
      label: Abnormal lacrimal duct morphology
  frequency: OCCASIONAL
  diagnostic: true
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several subjects with Ohdo also have lacrimal duct abnormalities."
    explanation: Lacrimal duct abnormalities are reported in several (a subset of) SBBYSS subjects, consistent with an OCCASIONAL band.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."
    explanation: Establishes lacrimal duct anomalies as SBBYSS-specific within the KAT6B disorders, supporting their diagnostic value.
- category: Dental
  name: Dental anomalies
  description: >
    Dental anomalies, particularly hypoplastic teeth, were emphasised as a
    salient feature of SBBYSS in the early literature and remain a significant
    discriminating feature of KAT6B-related disorders.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  frequency: FREQUENT
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental anomalies, particularly hypoplastic teeth, emphasised as a salient feature of SBBS in the early literature, were reported as present in only 21/44 individuals with KAT6B variants though they were a significant distinguishing feature."
    explanation: 21/44 (48%) of KAT6B-variant individuals had dental anomalies, which maps to the FREQUENT (30-79%) band.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental anomalies, thyroid anomalies, and hearing loss are seen in both syndromes, but more frequently in SBBYSS."
    explanation: Confirms dental anomalies are enriched in SBBYSS relative to GPS.
- category: Auditory
  name: Sensorineural hearing loss
  description: >
    Hearing loss, usually sensorineural, affects around a third of individuals
    with pathogenic KAT6B variants and warrants annual audiological
    surveillance.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss, often remarked upon in the early literature on SBBS was present in around a third of individuals with likely pathogenic KAT6B variants and was usually sensori-neural in origin."
    explanation: Around one third of KAT6B-variant individuals had usually sensorineural hearing loss, mapping to the FREQUENT (30-79%) band.
- category: Craniofacial
  name: Cleft palate
  description: >
    Cleft palate occurs in a substantial minority of individuals with KAT6B
    variants and contributes to feeding difficulties; SBBYSS therefore merits
    consideration in the differential diagnosis of syndromic clefting.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  frequency: FREQUENT
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cleft palate was seen in 14/44 patients, drawing attention to the fact that SBBS and GPS deserve consideration as a differential diagnosis for syndromic clefting."
    explanation: 14/44 patients = 32%, which falls in the FREQUENT band (30-79%). Caveat, the denominator mixes SBBS and GPS patients, so the SBBYSS-specific rate is not separately reported and the estimate sits near the FREQUENT/OCCASIONAL boundary.
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate."
    explanation: Independently documents cleft palate in a subset of SBBYSS individuals.
- category: Gastrointestinal
  name: Feeding difficulties
  description: >
    Feeding difficulties are a major source of infant morbidity in SBBYSS,
    driven by hypotonia and, in some individuals, cleft palate, and often
    require feeding therapy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  frequency: FREQUENT
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding difficulties are seen in both conditions. Contributing factors may be hypotonia in both syndromes, laryngomalacia in a minority of GPS subjects and cleft palate in some individuals with SBBYSS."
    explanation: Documents feeding difficulties in SBBYSS and identifies hypotonia and cleft palate as contributing factors.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients."
    explanation: Feeding difficulties statistically discriminate KAT6B-variant-positive patients.
- category: Cardiovascular
  name: Congenital heart defects
  description: >
    Congenital heart defects affect about half of individuals with a
    KAT6B disorder, most commonly atrial and ventricular septal defects,
    patent foramen ovale and patent ductus arteriosus.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart defects are noted in about 50% of subjects with either syndrome, the most frequent defects being atrial septal defects, ventricular septal defects, and a patent foramen ovale."
    explanation: About 50% frequency maps directly to the FREQUENT (30-79%) band and names the commonest lesions.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The commonest cardiac anomalies observed in the KAT6B-positive group were atrial and ventricular septal defects and patent ductus arteriosus"
    explanation: Independently characterises the cardiac lesion spectrum in KAT6B-variant-positive patients.
- category: Genitourinary
  name: Cryptorchidism
  description: >
    Genital anomalies, usually cryptorchidism, are essentially universal in
    males with a pathogenic KAT6B variant; unlike genitopatellar syndrome,
    scrotal hypoplasia and ambiguous genitalia are not features of SBBYSS.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genital anomalies, usually cryptorchidism, was universal in males with KAT6B sequence variants and tended to be more severe in GPS, where the genitalia may be ambiguous."
    explanation: Cryptorchidism was universal in KAT6B-variant males, supporting the VERY_FREQUENT band, with the more severe ambiguous-genitalia end restricted to GPS.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cryptorchidism is seen in both conditions but scrotal hypoplasia has only been reported in GPS."
    explanation: Confirms cryptorchidism in SBBYSS and separates it from GPS-restricted scrotal hypoplasia.
- category: Musculoskeletal
  name: Joint hypermobility
  description: >
    Joint laxity is a usual presenting feature of SBBYSS, in contrast to the
    large-joint flexion contractures that characterise the allelic
    genitopatellar syndrome.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  frequency: FREQUENT
  evidence:
  - reference: PMID:37658610
    reference_title: "Clinical heterogeneity of polish patients with KAT6B-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes."
    explanation: Joint laxity is listed among the features SBBYSS individuals "usually present with"; "usually" maps to the FREQUENT band under the qualitative-term mapping.
- category: Skeletal
  name: Talipes
  description: >
    In SBBYSS, joint contractures are less severe than in genitopatellar
    syndrome and manifest more frequently as talipes and overlapping fingers
    and toes rather than large-joint contractures.
  phenotype_term:
    preferred_term: Talipes
    term:
      id: HP:0001883
      label: Talipes
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In SBBS, the joint contractures were less severe and manifested more frequently as talipes and overlapping fingers and toes"
    explanation: Identifies talipes as the characteristic SBBYSS form of limb positional anomaly, contrasted with GPS large-joint contractures. The source gives only a comparative statement with no numerator or frequency term, so the OCCASIONAL band is a conservative curator estimate rather than a sourced figure.
- category: Ophthalmologic
  name: Keratoconus
  description: >
    Concern for keratoconus was identified in an expanded KAT6B cohort as an
    additional phenotype occurring in greater numbers than previously reported,
    adding a further ophthalmological manifestation to the SBBYSS eye
    phenotype.
  phenotype_term:
    preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
  evidence:
  - reference: PMID:34519438
    reference_title: "Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported."
    explanation: An expanded KAT6B-spectrum cohort reports keratoconus among newly recognised phenotypes; the source gives no denominator, so no frequency band is assigned.
- category: Immunologic
  name: Recurrent infections
  description: >
    Recurring infections were identified in an expanded KAT6B cohort in greater
    numbers than previously reported, and are a practical management concern in
    medically fragile children with this disorder.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:34519438
    reference_title: "Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported."
    explanation: An expanded KAT6B-spectrum cohort reports recurring infections among newly recognised phenotypes; no denominator is given, so no frequency band is assigned.
- category: Skeletal
  name: Increased fracture susceptibility
  description: >
    Fractures were reported in greater numbers than previously recognised in an
    expanded KAT6B cohort, consistent with the abnormal ossification programme
    demonstrated in Kat6b-deleted mice.
  phenotype_term:
    preferred_term: Increased susceptibility to fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:34519438
    reference_title: "Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported."
    explanation: An expanded KAT6B-spectrum cohort reports fractures among newly recognised phenotypes; no denominator is given, so no frequency band is assigned.
- category: Neurologic
  name: Neurobehavioral difficulties
  description: >
    Neurobehavioral difficulties, including autism-like behaviour, poor eye
    contact and attention problems, are more frequent in the KAT6B disorders
    than the early SBBYSS literature indicated. This is the human counterpart
    of the sociability deficit that the Kat6b-haploinsufficient mouse model
    displays and that acetylation-restoring treatment partially rescues.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported."
    explanation: Establishes neurobehavioural difficulties as an under-recognised but recurrent feature of the KAT6B disorder spectrum including SBBYSS.
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals."
    explanation: Model-organism corroboration only, the KAT6B-haploinsufficient mouse shows social deficits that the authors describe as mirroring SBBYSS individuals; this supports the mechanistic link but is not human evidence for the phenotype.
- category: Neurologic
  name: Cerebral anomalies
  description: >
    Structural brain anomalies, including corpus callosum hypoplasia or
    agenesis and altered myelination, occur in the KAT6B disorders more often
    than initially reported, although brain MRI can be normal. Corpus callosum
    agenesis is far more characteristic of the allelic genitopatellar syndrome.
  phenotype_term:
    preferred_term: Abnormal brain morphology
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported."
    explanation: Establishes cerebral anomalies as an under-recognised but recurrent feature of the KAT6B disorder spectrum including SBBYSS.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Several patients with SBBS had either agenesis of the corpus callosum, hydronephrosis and joint contractures, features more typical of GPS."
    explanation: Documents structural brain involvement specifically in SBBYSS patients, while noting it is more typical of the allelic GPS.
- category: Growth
  name: Slow growth
  description: >
    Slow postnatal growth is observed across the KAT6B disorder spectrum,
    including SBBYSS, and compounds the feeding difficulties of infancy.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype."
    explanation: GeneReviews lists slow growth among the features observed in individuals with either KAT6B phenotype, including SBBYSS.
- category: Gastrointestinal
  name: Small bowel malrotation
  description: >
    Malrotation of the small bowel is a recognised structural gastrointestinal
    anomaly of the KAT6B disorders and has been observed in individuals with
    KAT6B sequence variants; it is uncommon but surgically important.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  frequency: VERY_RARE
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype."
    explanation: GeneReviews lists small bowel malrotation among the features observed in individuals with either KAT6B phenotype, including SBBYSS.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An interesting observation was the presence of malrotation of the bowel in two patients with KAT6B sequence variants."
    explanation: Two of the 57-patient KAT6B cohort had bowel malrotation, supporting the VERY_RARE frequency band.
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intestinal malrotation and its serious consequences can be present in affected individuals."
    explanation: A 32-individual KAT6B cohort confirms intestinal malrotation as a clinically consequential feature of the KAT6B disorder spectrum.
- category: Ophthalmologic
  name: Optic nerve hypoplasia
  description: >
    Optic nerve hypoplasia is part of the ophthalmological involvement of the
    KAT6B disorders and, together with cerebral anomalies and neurobehavioural
    difficulties, is more frequent than the early SBBYSS literature suggested.
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported."
    explanation: Establishes optic nerve hypoplasia as an under-recognised but recurrent feature of the KAT6B disorder spectrum including SBBYSS.
- category: Skeletal
  name: Postaxial polydactyly
  description: >
    Distal limb anomalies beyond the characteristic long thumbs and great toes,
    including polydactyly, occur in the KAT6B disorder spectrum more often than
    the early literature indicated. This reconciles the legacy Orphanet/MONDO
    definition of the SBBYS-type blepharophimosis-intellectual disability
    syndrome, which lists postaxial polydactyly, with the modern KAT6B-era
    phenotype description.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:32424177
    reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported"
    explanation: Documents polydactyly as a recognised, under-reported distal limb anomaly of the KAT6B disorder spectrum.
  - reference: ORPHA:3047
    reference_title: Blepharophimosis-intellectual disability syndrome, SBBYS type (Orphanet structured-database record)
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "skeletal involvement (polydactyly, long thumb(s) and long first toe(s), and patellar hypoplasia/agenesis)"
    explanation: Orphanet's structured record for the SBBYS type lists polydactyly among the skeletal involvement, consistent with the KAT6B cohort finding; the record does not specify the postaxial subtype, hence PARTIAL.
- category: Craniofacial
  name: Bulbous nasal tip
  description: >
    A bulbous nasal tip with a broad nasal bridge, small mouth, thin upper lip
    and small low-set ears completes the recognisable SBBYSS facial gestalt.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients have a distinctive mask-like face with severe blepharophimosis and ptosis, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip and small, low set ears."
    explanation: The bulbous nasal tip is described as a feature of the "typical" SBBYSS facial gestalt in a 57-patient cohort; "typically" maps to the VERY_FREQUENT band, consistent with the identical mapping applied to blepharophimosis, ptosis and mask-like facies from this same sentence.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is characterized by blepharophimosis, ptosis, an immobile mask-like face, a bulbous nasal tip, hypotonia, feeding problems, long thumbs and great toes, and dislocated or hypoplastic patellae"
    explanation: The bulbous nasal tip is part of the canonical SBBYS clinical description.
genetic:
- name: KAT6B
  gene_term:
    preferred_term: KAT6B
    term:
      id: hgnc:17582
      label: KAT6B
  association: CAUSAL
  variant_origin: DE_NOVO
  inheritance:
  - name: Autosomal dominant
    description: >
      SBBYSS occurs sporadically as an autosomal dominant condition; nearly all
      pathogenic KAT6B variants arise de novo, so recurrence risk for most
      families is low. A single reported family with two affected siblings born
      to non-carrier parents is presumed to reflect gonadal mosaicism, and
      prenatal testing should still be offered. Rare true transmission is
      nonetheless documented: an individual has been reported whose pathogenic
      variant was inherited from a mildly affected parent, so parental testing
      and examination should not be omitted.
    de_novo_rate: ">95"
    evidence:
    - reference: PMID:23236640
      reference_title: "KAT6B Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KAT6B disorders are inherited in an autosomal dominant manner. To date, most individuals with a KAT6B disorder have had a de novo pathogenic variant."
      explanation: GeneReviews establishes autosomal dominant inheritance with predominantly de novo occurrence.
    - reference: PMID:25424711
      reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Apart from one family, reported so far, where two affected siblings were born to parents who did not carry the variant in blood, and where gonadal mosaicism was presumed, all KAT6B variants have occurred de novo and recurrence risks for most families are low, though prenatal testing should be offered as an option."
      explanation: Quantifies the near-universal de novo origin and documents the single presumed gonadal-mosaicism family, supporting the high de novo rate.
    - reference: PMID:32424177
      reference_title: "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "We also report an individual in which a pathogenic variant was inherited from a mildly affected parent."
      explanation: Documents genuine parent-to-child transmission with variable expressivity, qualifying the otherwise near-universal de novo origin.
    - reference: PMID:22077973
      reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations."
      explanation: Documents the sporadic occurrence and new dominant mutation basis of SBBYSS.
  features: >
    SBBYSS results from heterozygous protein-truncating variants in KAT6B
    (10q22.2). Most cluster in the large terminal exon (exon 18), which encodes
    a highly conserved serine- and methionine-rich transcriptional activation
    domain, but variants also occur in exons 15, 16 and 17 and more proximally.
    Two mechanistically distinct positions produce SBBYSS: proximal variants
    subject to nonsense-mediated decay (haploinsufficiency) and variants distal
    to the genitopatellar-syndrome cluster within exon 18. A recurrent de novo
    synonymous variant, c.3147G>A p.(Pro1049Pro) in exon 16, causes SBBYSS by
    creating a cryptic exonic splice acceptor site and is a mutational hot spot.
    Rare whole-gene deletions and translocations disrupting KAT6B produce a
    much milder blepharophimosis-intellectual disability phenotype rather than
    classic SBBYSS.
  evidence:
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS."
    explanation: Identifies KAT6B as the causal gene of SBBYSS with truncating variants clustering in the final exon.
  - reference: PMID:26334766
    reference_title: "A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation."
    explanation: Confirms the exon 18 clustering and near-exclusive protein-truncating nature of SBBYSS alleles.
  - reference: PMID:26334766
    reference_title: "A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant."
    explanation: Functional RNA evidence that the recurrent exon 16 synonymous variant acts by creating a cryptic splice acceptor site.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo."
    explanation: A 57-patient cohort confirms terminal-exon localisation and de novo origin of causative KAT6B variants.
  - reference: PMID:28857140
    reference_title: "Say-Barber-Biesecker-Young-Simpson syndrome and Genitopatellar syndrome: Lumping or splitting?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities."
    explanation: Supports a positional genotype-phenotype correlation that keeps SBBYSS and genitopatellar syndrome as distinct entities.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    No population-based prevalence estimate exists for SBBYSS. The condition is
    known only from case reports and small cohorts; the largest single
    ascertainment identified likely causative KAT6B variants in 34 of 57
    referred patients. A 2025 systematic review of the literature counted only
    152 molecularly confirmed KAT6B-related disorder patients across 33 papers,
    of whom the SBBYSS subgroup is a fraction. Orphanet does not publish a
    prevalence class for ORPHA:3047.
  evidence:
  - reference: PMID:40277451
    reference_title: "Phenotypic Characterization of Seven Pediatric Patients Diagnosed With KAT6B-Related Disorders: Case Series and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed a review of the literature, listing the clinical features of 152 patients described in 33 papers, with a molecularly confirmed diagnosis of KAT6B-related disorders"
    explanation: A complete literature census of only 152 molecularly confirmed KAT6B-related disorder patients supports an ultra-rare, cases-in-literature characterisation.
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients"
    explanation: The largest published ascertainment reports only tens of molecularly confirmed cases, supporting an ultra-rare, literature-case-count characterisation rather than a population rate.
diagnosis:
- name: KAT6B molecular genetic testing
  description: >-
    The diagnosis is established by identifying a heterozygous pathogenic KAT6B
    variant, in practice by exome sequencing or targeted KAT6B sequencing
    covering all coding exons and splice junctions rather than exon 18 alone.
    Conventional karyotype and chromosomal microarray are frequently normal in
    SBBYSS, so a normal cytogenetic result does not exclude the diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28232779
    reference_title: "De novo KAT6B Mutation Identified with Whole-Exome Sequencing in a Girl with Say-Barber/Biesecker/Young-Simpson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If a patient is suspected of having a blepharophimosis syndrome or SBBYSS, we recommend sequencing the KAT6B gene."
    explanation: States the diagnostic recommendation to sequence KAT6B when SBBYSS or a blepharophimosis syndrome is suspected.
  - reference: PMID:28232779
    reference_title: "De novo KAT6B Mutation Identified with Whole-Exome Sequencing in a Girl with Say-Barber/Biesecker/Young-Simpson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previous genetic testing (array-CGH, 22q11 deletion, PTPN11 and MLL2 mutation analysis) gave normal results. We performed whole-exome sequencing (WES) and identified a heterozygous nonsense mutation in the KAT6B gene"
    explanation: Illustrates that array-CGH and targeted panels can be normal in SBBYSS and that exome sequencing is the effective diagnostic route.
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of a KAT6B disorder is established by the identification of a heterozygous pathogenic variant in KAT6B on molecular genetic testing."
    explanation: GeneReviews defines molecular identification of a heterozygous pathogenic KAT6B variant as the diagnostic standard.
- name: DNA methylation episignature
  description: >-
    A peripheral-blood genome-wide DNA methylation episignature specific to
    KAT6B-related disorders has been described and can differentiate the two
    KAT6B neurodevelopmental disorders from the highly overlapping KAT6A
    syndrome. It is a downstream biomarker of chromatin-regulator dysfunction
    rather than the causal lesion, and its main curated use is supporting
    reclassification of variants of uncertain significance.
  diagnosis_term:
    preferred_term: genome-wide DNA methylation (episignature) analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  evidence:
  - reference: PMID:37249002
    reference_title: "DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (KAT6A), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B (KAT6B)."
    explanation: Establishes that a distinct DNA methylation episignature exists for the KAT6B-related neurodevelopmental disorders, including SBBYSS.
  - reference: PMID:37249002
    reference_title: "DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate the ability of our models to differentiate between highly overlapping episignatures, increasing the ability to effectively identify and diagnose these conditions."
    explanation: Supports the discriminating diagnostic utility of the episignature across the closely related KAT6A and KAT6B disorders.
treatments:
- name: Multidisciplinary supportive and rehabilitative care
  description: >
    No disease-modifying therapy exists for SBBYSS. Management is supportive
    and multidisciplinary, with referral to an early-intervention programme for
    occupational, physical, speech and feeding therapy beginning in infancy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy."
    explanation: GeneReviews recommends multidisciplinary early-intervention supportive care as the standard of management for KAT6B disorders including SBBYSS.
- name: Thyroid hormone replacement for congenital hypothyroidism
  description: >
    Congenital hypothyroidism associated with a KAT6B disorder is treated in
    the standard manner by the appropriate specialist, i.e. with thyroid
    hormone replacement, and thyroid function requires annual monitoring
    because hypothyroidism may present or recur after the neonatal period.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
  treatment_term:
    preferred_term: thyroid hormone replacement therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: CHEBI:18332
        label: L-thyroxine
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with KAT6B disorders are treated or managed in the standard manner by the appropriate specialist."
    explanation: GeneReviews directs that hypothyroidism in KAT6B disorders be treated in the standard manner by the appropriate specialist.
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitoring for hearing loss, amblyopia, hypothyroidism, and contractures and/or scoliosis should occur annually"
    explanation: GeneReviews specifies annual surveillance for hypothyroidism, supporting ongoing endocrine management.
- name: Annual multisystem surveillance
  description: >
    Annual surveillance covers developmental progress and educational needs,
    feeding, and screening for hearing loss, amblyopia, hypothyroidism, and
    contractures and/or scoliosis. Cardiac and renal function are evaluated and
    monitored as needed when a malformation is present.
  treatment_term:
    preferred_term: clinical surveillance screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evaluations of developmental progress and educational needs, assessment for feeding issues, and monitoring for hearing loss, amblyopia, hypothyroidism, and contractures and/or scoliosis should occur annually."
    explanation: GeneReviews defines the annual surveillance schedule for KAT6B disorders.
- name: Physical therapy
  description: >
    Physical therapy is used to increase joint mobility, and orthopedic
    intervention is undertaken as needed for contractures and clubfoot.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic intervention as needed for contractures and clubfoot; physical therapy to increase joint mobility."
    explanation: GeneReviews recommends physical therapy to improve joint mobility in KAT6B disorders.
- name: Speech and language therapy
  description: >
    Referral to an early intervention program from infancy is recommended so
    that speech and language therapy can begin early, addressing the severely
    delayed or absent speech that is a defining SBBYSS feature.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy."
    explanation: GeneReviews recommends early-intervention speech therapy from infancy in KAT6B disorders.
- name: Occupational therapy
  description: >
    Occupational therapy is delivered through the same early intervention
    referral and targets the functional consequences of hypotonia, joint laxity
    and distal limb anomalies on fine motor skills and activities of daily
    living.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy."
    explanation: GeneReviews recommends early-intervention occupational therapy from infancy in KAT6B disorders.
- name: Surgical correction of congenital anomalies
  description: >
    Medical problems associated with gastrointestinal, genitourinary, cardiac,
    palatal or dental anomalies, and lacrimal duct abnormalities, are treated
    or managed in the standard manner by the appropriate specialist, which for
    many SBBYSS features means surgical correction (e.g. cleft palate repair,
    orchidopexy, cardiac repair, lacrimal duct probing).
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal or dental anomalies; abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with KAT6B disorders are treated or managed in the standard manner by the appropriate specialist."
    explanation: GeneReviews assigns standard specialist (frequently surgical) management to the structural anomalies of KAT6B disorders.
- name: Genetic counseling
  description: >
    Genetic counseling addresses autosomal dominant, almost always de novo,
    causation, the resulting low recurrence risk, presumed gonadal mosaicism in
    a single reported family, and reproductive options. Prenatal and
    preimplantation genetic testing are possible once the familial variant is
    known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified."
    explanation: GeneReviews documents the genetic counseling and prenatal/preimplantation testing options for KAT6B disorders.
- name: Histone-acetylation-restoring therapy (experimental / preclinical)
  description: >
    A preclinical proof-of-principle strategy targets the core epigenetic
    lesion of SBBYSS by restoring histone acetylation. In human cells carrying
    SBBYSS-specific KAT6B mutations and in Kat6b heterozygous mice, the histone
    deacetylase inhibitor valproic acid and the acetyl donor acetyl-carnitine
    (ALCAR) elevated histone acetylation, partially reversed cortical neuronal
    gene-expression changes, improved sociability, and (for ALCAR) restored
    learning and memory. This is postnatal, disease-mechanism-directed therapy
    and is NOT yet clinically validated in humans with SBBYSS.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Reduced histone acetylation and transcriptional dysregulation
    treatment_effect: RESTORES
    description: >-
      Valproic acid (an HDAC inhibitor) and acetyl-carnitine (an acetyl donor)
      act directly on the reduced-histone-acetylation node, raising histone
      acetylation and partially reversing the downstream transcriptional
      dysregulation in KAT6B-deficient cells and mice.
    evidence:
    - reference: PMID:38557491
      reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory."
      explanation: Confirms that acting on the reduced-acetylation node produces measurable rescue of the downstream neurobehavioural phenotype.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory."
    explanation: Preclinical mouse evidence that restoring histone acetylation partially rescues the neurobehavioural phenotype of KAT6B haploinsufficiency.
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions."
    explanation: The authors frame the finding as a hypothesis for a subset of SBBYSS individuals, so the evidence is preclinical and not a validated clinical recommendation.
  - reference: PMID:40083716
    reference_title: "KAT6B overexpression in mice causes aggression, anxiety, and epilepsy."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Our results suggest that, in addition to loss-of-function alleles, gain-of-function KAT6B alleles may be detrimental for brain development."
    explanation: Dosage-sensitivity caveat on this strategy. Because excess KAT6B activity is itself detrimental to brain development, raising KAT6B-dependent acetylation has a two-sided therapeutic window, further limiting the strategy to preclinical status.
  - reference: PMID:40083716
    reference_title: "KAT6B overexpression in mice causes aggression, anxiety, and epilepsy."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Kat6b overexpression led to an increase in histone H3 lysine 9 acetylation and upregulation of genes driving nervous system development and neuronal differentiation."
    explanation: Shows that the same H3K9 acetylation mark this therapy aims to restore produces an adverse neurobehavioural phenotype when driven above normal, defining the upper bound of the therapeutic window.
differential_diagnoses:
- name: Genitopatellar syndrome
  description: >
    The allelic KAT6B disorder at the severe end of the spectrum
    (MONDO:0011640), curated separately in this knowledge base. GPS is
    distinguished from SBBYSS by large-joint flexion contractures, anomalies of
    the spine, ribs and pelvis, renal cysts and hydronephrosis, and agenesis of
    the corpus callosum, which are markedly more frequent and more severe in
    GPS. These are differences of degree rather than absolute discriminators:
    GeneReviews describes patellar hypoplasia/agenesis, flexion contractures of
    the knees and/or hips and anomalies of the digits, spine and/or ribs as
    features of both KAT6B phenotypes, and individual SBBYSS patients with
    corpus callosum agenesis, hydronephrosis or joint contractures are on
    record. In SBBYSS the contractures are less severe and present more often
    as talipes and overlapping digits than as large-joint contractures. Corpus
    callosum involvement is the nearest thing to a hard discriminator. Long
    thumbs/great toes and lacrimal duct anomalies, conversely, occur only in
    SBBYSS. GPS-causing variants sit in the proximal portion of the last
    exon, SBBYSS-causing variants proximal to the last exon or more distally
    within it. Overlapping intermediate phenotypes are increasingly recognised
    under the umbrella "KAT6B spectrum disorders".
  disease_term:
    preferred_term: Genitopatellar Syndrome
    term:
      id: MONDO:0011640
      label: genitopatellar syndrome
  evidence:
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis, and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities."
    explanation: Enumerates the discriminating features that separate SBBYSS from the allelic genitopatellar syndrome.
  - reference: PMID:22715153
    reference_title: "The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A thin or absent corpus callosum is seen in all subjects with GPS whereas this anomaly has not been observed in SBBYSS."
    explanation: Corpus callosum involvement is the strongest single discriminator between GPS and SBBYSS in the 2012 series, though later cohorts qualify it (see the PARTIAL item below).
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Several patients with SBBS had either agenesis of the corpus callosum, hydronephrosis and joint contractures, features more typical of GPS."
    explanation: Qualifies the discriminators, a later and larger cohort found SBBYSS patients with corpus callosum agenesis, hydronephrosis and joint contractures, so these separate the two entities by frequency and severity rather than absolutely.
  - reference: PMID:23236640
    reference_title: "KAT6B Disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs."
    explanation: GeneReviews attributes patellar, contracture and spine/rib anomalies to both KAT6B phenotypes, confirming that these are shared features differing in degree rather than GPS-exclusive ones.
- name: X-linked Ohdo syndrome (Maat-Kievit-Brunner type)
  description: >
    A genetically distinct blepharophimosis-intellectual disability syndrome
    caused by MED12 variants, not KAT6B. It shares blepharophimosis and
    intellectual disability with SBBYSS but is X-linked and lacks the KAT6B
    facial gestalt, long thumbs/great toes, patellar anomalies and thyroid
    involvement. Distinguishing it from SBBYSS is essential because the
    umbrella term "Ohdo syndrome" spans several genetically separate entities.
  evidence:
  - reference: PMID:25424711
    reference_title: "Further delineation of the KAT6B molecular and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The remaining groups comprised the original patients reported by Ohdo et al,15 The X-linked disorder originally reported by Maat-Kievit et al16 and now known to be due to sequence variants within the MED12 gene,17 and a recessive entity associated with microcephaly and multiple structural anomalies."
    explanation: Documents that the blepharophimosis-intellectual disability group contains genetically distinct entities including the MED12-related X-linked Ohdo syndrome, which must be separated from KAT6B-related SBBYSS.
animal_models:
- species: Mouse (Mus musculus)
  genotype: Germline Kat6b heterozygous (Kat6b+/-) mouse
  category: Knockout
  genes:
  - preferred_term: Kat6b (KAT6B)
    term:
      id: hgnc:17582
      label: KAT6B
  description: >
    A germline Kat6b heterozygous mouse models the haploinsufficiency class of
    SBBYSS alleles. Kat6b+/- mice show reduced histone H3K9 acetylation and
    learning, memory and social deficits that mirror SBBYSS individuals, and
    they respond to acetylation-restoring pharmacotherapy, making this the
    primary preclinical model for SBBYSS therapeutic development.
  associated_phenotypes:
  - Learning and memory deficits
  - Social behaviour deficits
  - Reduced histone H3K9 acetylation
  evidence:
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment."
    explanation: Explicitly establishes the Kat6b heterozygous mouse as a model of SBBYSS with the matching OMIM identifier.
  - reference: PMID:38557491
    reference_title: "Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals."
    explanation: Documents face validity of the model for the SBBYSS neurodevelopmental phenotype.
- species: Mouse (Mus musculus)
  genotype: Qkf (querkopf) hypomorphic Kat6b mouse
  category: Hypomorph
  genes:
  - preferred_term: Kat6b (KAT6B)
    term:
      id: hgnc:17582
      label: KAT6B
  description: >
    The Qkf mouse is a hypomorphic Kat6b mutant whose small eyes, ventrally
    placed ears and long first digits recapitulate the periocular, ear and
    long-thumb/great-toe features of SBBYSS.
  associated_phenotypes:
  - Small eyes
  - Ventrally placed ears
  - Long first digits
  evidence:
  - reference: PMID:22077973
    reference_title: "Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype."
    explanation: Establishes the Qkf hypomorph as a mouse model whose features mirror the human SBBYSS phenotype.
experimental_models:
- name: KMUGMCi008-A patient-derived induced pluripotent stem cell line
  description: >-
    A human induced pluripotent stem cell line reprogrammed from peripheral
    blood mononuclear cells of an individual with the SBBYS variant of Ohdo
    syndrome carrying a heterozygous KAT6B frameshift variant, generated with
    Sendai-virus reprogramming. It provides a patient-genotype human cellular
    system for in vitro disease modelling of SBBYSS, complementing the
    CRISPR-engineered KAT6B cell lines and the Kat6b mouse models.
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: Patient-derived peripheral blood mononuclear cells
  publication: PMID:39986017
  evidence:
  - reference: PMID:39986017
    reference_title: "Establishment of a human induced pluripotent stem cell line, KMUGMCi008-A, from a patient with A Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome bearing heterozygous frameshift mutation in the KAT6B gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The peripheral blood mononuclear cells from a patient carrying heterozygous frameshift mutation of the KAT6B gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit."
    explanation: Documents the derivation of the patient iPSC line from an SBBYSS individual with a heterozygous KAT6B frameshift variant.
  - reference: PMID:39986017
    reference_title: "Establishment of a human induced pluripotent stem cell line, KMUGMCi008-A, from a patient with A Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome bearing heterozygous frameshift mutation in the KAT6B gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The established human induced pluripotent cell line allow proper in vitro disease modelling of Ohdo syndrome SBBYS variant."
    explanation: States the intended use of the line as an in vitro disease model of the SBBYS variant of Ohdo syndrome.
notes: >
  SBBYSS (MONDO:0011365; OMIM:603736; ORPHA:3047) is allelic with genitopatellar
  syndrome (GPS; MONDO:0011640; OMIM:606170), which is curated separately at
  kb/disorders/Genitopatellar_Syndrome.yaml. This entry deliberately models
  SBBYSS as the distinct milder entity: the discriminating SBBYSS features
  (mask-like facies, blepharophimosis/ptosis, long thumbs and great toes,
  lacrimal duct anomalies, congenital hypothyroidism, joint laxity, patellar
  hypoplasia/dislocation rather than aplasia) are curated here, while the
  GPS-restricted features (large-joint flexion contractures, spine/rib/pelvis
  anomalies, renal cysts and hydronephrosis, corpus callosum agenesis, scrotal
  hypoplasia) remain in the GPS entry and are recorded here only as
  differential-diagnosis discriminators.

  Naming and named-entity caution: "Ohdo syndrome" is an umbrella label
  covering several genetically distinct entities. Only the SBBYS variant is
  KAT6B-related. The X-linked Maat-Kievit-Brunner variant is caused by MED12
  variants (see differential diagnoses), the original patients reported by Ohdo
  et al. appear to have had a different condition, and a further recessive
  entity with microcephaly and multiple structural anomalies has been
  described. Literature retrieved under the bare term "Ohdo syndrome" must
  therefore be checked for gene identity before being used as SBBYSS evidence;
  no MED12-related publication is cited as SBBYSS evidence in this entry.

  Discrepancy in the source ontologies: the MONDO textual definition for
  MONDO:0011365 is inherited from an older Orphanet record and states that
  postaxial polydactyly is a feature and that "Autosomal recessive inheritance
  has been suggested". The inheritance statement is superseded by the KAT6B-era
  literature - SBBYSS is autosomal dominant with almost exclusively de novo
  truncating KAT6B variants - and the MONDO definition text is a candidate for
  an upstream fix on that point. The polydactyly statement, by contrast, is
  supported: the 2020 KAT6B cohort of Zhang et al. (PMID:32424177) found that
  distal limb anomalies other than long thumbs and great toes, including
  polydactyly, are more frequent than initially reported, and the current
  Orphanet ORPHA:3047 definition retains polydactyly among the skeletal
  involvement. Polydactyly is therefore curated here as a phenotype without a
  frequency band, rather than dismissed as a legacy error: the supporting
  sources establish the disease-phenotype association but give no denominator
  from which a band could be derived.

  Features present in the KAT6B literature but not promoted to structured
  phenotypes here include microcephaly (SBBYSS individuals often have a smaller
  than average head circumference but usually not frank microcephaly, unlike
  GPS), hypoplastic teeth as a specific dental subtype, and light/noise
  sensitivity. These should be promoted once a directly quotable snippet is
  sourced. Slow growth and small bowel malrotation were promoted on the
  strength of the GeneReviews KAT6B Disorders Clinical Characteristics
  statement (PMID:23236640); keratoconus, recurrent infections and increased
  fracture susceptibility were promoted from the expanded-cohort sentence in
  PMID:34519438; and cerebral anomalies, neurobehavioural difficulties, optic
  nerve hypoplasia and polydactyly were promoted from PMID:32424177. Each of
  these is sourced at the KAT6B-disorder-spectrum level rather than to an
  SBBYSS-only denominator, so none carries a frequency band.

  Frequency-band conventions used in this entry, for the phenotypes where no
  usable denominator exists (docs/frequency-evidence-guidelines.md Pattern D):
  Talipes retains an OCCASIONAL band because the band is declared in its
  evidence explanation as an explicit conservative curator estimate
  (Pattern D option 1). Patellar hypoplasia and postaxial polydactyly instead
  omit the band entirely (Pattern D option 2) - for patellar hypoplasia because
  the one quantitative figure (8/32) comes from a mixed GPS/SBBYSS cohort and
  contradicts the qualitative "typically involves" wording of the other
  sources, and for polydactyly because the source offers only a comparative
  statement at the KAT6B-spectrum level.

  Dosage caveat on the experimental acetylation-restoring strategy: KAT6B is
  dosage-sensitive in both directions. Kat6b haploinsufficiency causes the
  SBBYSS-like mouse phenotype, but KAT6B *overexpression* in mice causes
  aggression, anxiety and epilepsy (PMID:40083716). Any therapeutic aiming to
  raise KAT6B-dependent acetylation therefore has a two-sided therapeutic
  window, which reinforces that the valproic-acid / acetyl-carnitine data
  remain preclinical proof-of-principle rather than a clinical recommendation.
datasets: []

📚

References & Deep Research

References

PMID:23236640

KAT6B Disorders.

No top-level findings curated for this source.

Deep Research

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 28 citations 2026-07-31T00:52:42.472394

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Say-Barber-Biesecker-Young-Simpson Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Say-Barber-Biesecker-Young-Simpson Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Say–Barber–Biesecker–Young–Simpson syndrome: disease-characteristics report

Executive summary

Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS) is an ultra-rare, congenital, multisystem Mendelian chromatinopathy caused by a heterozygous pathogenic variant in KAT6B, usually arising de novo. It is best regarded as one part of a continuous KAT6B-related disorder spectrum that also includes genitopatellar syndrome (GPS) and intermediate phenotypes. Hallmarks are developmental delay/intellectual disability, hypotonia, blepharophimosis and ptosis, mask-like facial appearance, long thumbs/great toes, feeding difficulties, patellar abnormalities, and variably cardiac, genital, renal, thyroid, auditory, ocular, palatal, and cerebral anomalies. There is no curative or approved molecular therapy; current care is multidisciplinary and complication-directed. A major 2024 advance was proof-of-concept rescue of behavioral and molecular abnormalities in human cells and Kat6b-haploinsufficient mice by increasing histone acetylation, but this has not yet established efficacy or safety in patients. (bergamasco2024increasinghistoneacetylation pages 1-2, zhang2020furtherdelineationof pages 1-2, magdalena2023clinicalheterogeneityof pages 1-2)

The principal evidence is summarized below.

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) (zhang2020furtherdelineationof pages 1-2, shin2021aneonatewith pages 1-3, magdalena2023clinicalheterogeneityof pages 1-2)	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 (zhang2020furtherdelineationof pages 1-2, magdalena2023clinicalheterogeneityof pages 1-2)	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 (maglione2025phenotypiccharacterizationof pages 6-7, maglione2025phenotypiccharacterizationof pages 2-2)	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 (zhang2020furtherdelineationof pages 1-2, zhang2020furtherdelineationof pages 7-8, shin2021aneonatewith pages 1-3, davarnia2024denovokat6b pages 1-2)	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 (lundsgaard2017denovokat6b pages 1-2, shin2021aneonatewith pages 1-3, magdalena2023clinicalheterogeneityof pages 1-2)	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%) (zhang2020furtherdelineationof pages 4-5)	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 (zhang2020furtherdelineationof pages 4-5, zhang2020furtherdelineationof pages 1-2, zhang2020furtherdelineationof pages 7-8)	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 (zhang2020furtherdelineationof pages 1-2, zhang2020furtherdelineationof pages 7-8)	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 (zhang2020furtherdelineationof pages 7-8)	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 (bergamasco2024increasinghistoneacetylation pages 1-2, magdalena2023clinicalheterogeneityof pages 1-2)	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 (zhang2020furtherdelineationof pages 1-2, zu2022brpf1kat6akat6bcomplexmolecular pages 4-6, bergamasco2024increasinghistoneacetylation pages 1-2)	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 (magdalena2023clinicalheterogeneityof pages 1-2, magdalena2023clinicalheterogeneityof pages 10-10)	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 (bergamasco2024increasinghistoneacetylation pages 1-2, bergamasco2024increasinghistoneacetylation pages 15-17)	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 (bergamasco2024increasinghistoneacetylation pages 1-2, lundsgaard2017denovokat6b pages 1-2, zu2022brpf1kat6akat6bcomplexmolecular pages 4-6)	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 (lundsgaard2017denovokat6b pages 1-2, shin2021aneonatewith pages 1-3)	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 (zhang2020furtherdelineationof pages 7-8, shin2021aneonatewith pages 1-3, davarnia2024denovokat6b pages 1-2)	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 (zhang2020furtherdelineationof pages 7-8, shin2021aneonatewith pages 1-3)	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 (maglione2025phenotypiccharacterizationof pages 9-9, maglione2025phenotypiccharacterizationof pages 10-11)	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 (bergamasco2024increasinghistoneacetylation pages 1-2, zhang2020furtherdelineationof pages 7-8, magdalena2023clinicalheterogeneityof pages 1-2)	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.

1. Disease information

Definition and classification

SBBYSS is an autosomal-dominant multiple-congenital-anomaly and neurodevelopmental syndrome caused by pathogenic variation in KAT6B at chromosome 10q22.2. It belongs to the Mendelian chromatinopathies because KAT6B is a MYST-family lysine acetyltransferase that regulates developmentally important transcription. Increasing clinical overlap with GPS has led experts to favor the umbrella terms KAT6B-related disorder or KAT6B spectrum disorder, while retaining SBBYSS and GPS as useful clinical subtypes. (zhang2020furtherdelineationof pages 1-2, magdalena2023clinicalheterogeneityof pages 1-2)

Identifiers and nomenclature

OMIM: 603736.
Orphanet: ORPHA:3047.
MONDO: a dedicated MONDO mapping should be confirmed against the current MONDO release before database ingestion; the retrieved primary sources did not supply a MONDO identifier.
Related allelic disorder: genitopatellar syndrome, OMIM 606170.
Synonyms: SBBYSS; SBBYS syndrome; Say–Barber/Biesecker/Young–Simpson syndrome; Young–Simpson syndrome; Ohdo syndrome, SBBYS variant; Say–Barber–Biesecker–Young–Simpson variant of Ohdo syndrome.
ICD-10/ICD-11 and MeSH: no disease-specific code or descriptor was established in the retrieved sources. Coding generally requires broader congenital-malformation, intellectual-disability, or genetic-syndrome categories.

The report is based primarily on aggregated disease-level resources and published cohorts/case reports, not patient-level EHR data. The most informative human series comprised 32 previously unreported molecularly confirmed individuals; a later compilation identified 152 published molecularly confirmed KAT6B-spectrum cases—86 SBBYSS, 33 GPS, and 33 intermediate. (maglione2025phenotypiccharacterizationof pages 6-7, zhang2020furtherdelineationof pages 1-2)

2. Etiology, risk, and protective factors

Causal factor

The primary cause is a germline heterozygous pathogenic KAT6B variant. Most are truncating frameshift or nonsense variants; splice variants, rare missense variants, and larger loss-of-function alleles also occur. Zhang et al. catalogued 56 previously published variants and added 24: 14 frameshift, seven nonsense, one missense, and two intronic variants predicted to alter splicing. Most clustered in exon 18. (zhang2020furtherdelineationof pages 1-2, zhang2020furtherdelineationof pages 7-8)

Risk factors

Genetic: presence of a pathogenic KAT6B allele is the decisive risk factor. Most cases are sporadic and de novo, although rare mildly affected transmitting parents and multigenerational families demonstrate that inherited disease occurs. (zhang2020furtherdelineationof pages 1-2, zhang2020furtherdelineationof pages 7-8)
Parental age, sex, ancestry, consanguinity: no reproducible disease-specific associations are established.
Environmental, infectious, toxic, lifestyle, or occupational risks: none are known to cause SBBYSS.
Family history: usually absent, but becomes important where a parent is mildly affected or mosaic.

Protective factors and gene–environment interaction

No validated protective allele, modifier gene, diet, lifestyle intervention, or environmental exposure is known to prevent disease or reduce penetrance. Because the causal lesion acts during embryonic development, ordinary postnatal lifestyle modification cannot prevent the congenital syndrome. Acetyl-CoA availability and drugs affecting acetylation could theoretically modify downstream chromatin states, but this remains experimental rather than an established gene–environment interaction. The 2024 mouse study supports biochemical modifiability after birth but does not prove a human protective effect. (bergamasco2024increasinghistoneacetylation pages 15-17, bergamasco2024increasinghistoneacetylation pages 1-2)

3. Phenotypes

SBBYSS is recognizable at birth, but expression is variable and boundaries with GPS are imperfect. In the 2023 Polish series, all six patients had facial dysmorphism and developmental/speech delay; five of six had hypotonia, ocular abnormalities, and long thumbs. Knee abnormalities ranged from dysplasia and recurrent dislocation to subluxation rather than uniformly severe patellar agenesis. (magdalena2023clinicalheterogeneityof pages 1-2)

Core phenotype map

Domain	Manifestation, onset/course, and frequency evidence	Suggested HPO terms
Neurodevelopment	Global developmental delay and variable intellectual disability begin in infancy/childhood and are chronic. Speech is often disproportionately delayed; autism-like behavior, poor eye contact, ADHD traits, and seizures occur in subsets.	Global developmental delay (HP:0001263); Intellectual disability (HP:0001249); Delayed speech and language development; Autistic behavior; Seizure
Neuromuscular	Generalized hypotonia is usually congenital or infantile and contributes to delayed milestones and feeding problems. Contractures may occur, especially toward the GPS end of the spectrum.	Hypotonia (HP:0001252); Joint contracture
Craniofacial/ocular	Blepharophimosis, ptosis, mask-like immobile face, bulbous/tubular nose, broad nasal bridge, long philtrum, thin upper lip, micro/retrognathia, lacrimal-duct anomalies, strabismus, refractive errors, and optic-nerve hypoplasia.	Blepharophimosis (HP:0000581); Ptosis (HP:0000508); Mask-like facies; Bulbous nose; Lacrimal duct stenosis; Optic nerve hypoplasia
Skeletal/digital	Long thumbs/great toes are characteristic; patellar hypoplasia, agenesis, delayed ossification or displacement, scoliosis, clubfoot, hip/knee contractures, polydactyly, syndactyly, and other digital anomalies vary.	Long thumb; Long great toe; Patellar hypoplasia; Absent patella; Scoliosis; Clubfoot; Polydactyly
Feeding/GI/airway	Neonatal or infant feeding difficulty, reflux, recurrent emesis, constipation, laryngomalacia and respiratory problems occur. Intestinal malrotation is uncommon but potentially fatal.	Feeding difficulties; Gastroesophageal reflux; Constipation; Intestinal malrotation; Laryngomalacia
Cardiac	Congenital heart disease, especially atrial/ventricular septal defect, patent ductus arteriosus or patent foramen ovale. Arrhythmia is occasionally reported.	Atrial septal defect; Ventricular septal defect; Patent ductus arteriosus
Genitourinary	Cryptorchidism, micropenis, scrotal hypoplasia, hypospadias, testicular agenesis, clitoromegaly or labial hypoplasia; renal dysplasia/hypoplasia, hydronephrosis and reflux occur more often toward GPS.	Cryptorchidism (HP:0000028); Micropenis; Hypospadias; Renal hypoplasia; Hydronephrosis
Endocrine	Congenital or later hypothyroidism is recurrent and treatable. Delayed puberty/hypogonadism may occur.	Congenital hypothyroidism; Hypogonadism; Delayed puberty
Hearing/dental/palatal	Sensorineural or conductive hearing loss, delayed or absent/hypoplastic teeth, cleft or high-arched palate, and occasionally Pierre Robin sequence.	Sensorineural hearing impairment; Hypodontia; Delayed eruption of teeth; Cleft palate; High-arched palate
CNS imaging	Corpus-callosum agenesis/hypoplasia, microcephaly, altered myelination, and other cerebral anomalies, though MRI can be normal.	Agenesis of corpus callosum; Abnormality of cerebral white matter; Microcephaly

In the 32-person Zhang cohort, cleft/high-arched palate occurred in 14/32 (44%), patellar abnormalities in 8/32 (25%), other digital anomalies in 12/32 (38%), and congenital heart defects in 15/32 (47%). Among clinically classified SBBYSS cases with available data, long thumbs and/or great toes occurred in 12/15 (80%). Feeding difficulty, reflux or recurrent emesis affected nine individuals. Published-series estimates must be interpreted cautiously because ascertainment, missingness, and subtype assignment differ. (zhang2020furtherdelineationof pages 4-5)

Functional and quality-of-life effects

No validated SBBYSS-specific EQ-5D, SF-36, PROMIS, or natural-history quality-of-life dataset was found. Nevertheless, developmental and speech impairment, hypotonia, feeding dependence, hearing/vision loss, orthopedic abnormalities, behavioral problems, and congenital-organ disease can substantially limit communication, mobility, education, self-care, and independent living. A 14-year-old reported in 2024 required institutional support, physiotherapy, and speech therapy and lacked sphincter control, illustrating severe—but not universal—functional impact. (davarnia2024denovokat6b pages 1-2)

4. Genetic and molecular information

Causal gene

Gene: KAT6B, lysine acetyltransferase 6B.
Location: chromosome 10q22.2.
Aliases: MYST4, MORF; mouse ortholog Kat6b/Querkopf or Qkf.
Protein: a nuclear chromatin-associated MYST-family acetyltransferase with NEMM, tandem PHD, catalytic MYST, acidic, and serine/methionine-rich regions. (bergamasco2024increasinghistoneacetylation pages 1-2, zhang2020furtherdelineationof pages 7-8)

Variant architecture and consequence

Most clinically causal alleles are germline and heterozygous. Somatic KAT6B alterations reported in cancer are biologically distinct and do not define SBBYSS. Pathogenic germline truncating variants are expected to be absent or extremely rare in population databases; however, individual gnomAD frequencies should be checked against the precise transcript and genome build during clinical interpretation.

The prevailing allelic model is location dependent:

Upstream truncating alleles may trigger nonsense-mediated decay (NMD), reducing KAT6B dosage and causing haploinsufficiency.
Penultimate/final-exon truncations may escape NMD and produce abnormal truncated proteins, potentially exerting dominant-negative or altered-function effects.
This framework explains some genotype–phenotype differences but remains incompletely validated for individual mutant proteins. (bergamasco2024increasinghistoneacetylation pages 1-2, magdalena2023clinicalheterogeneityof pages 1-2)

Variants in proximal exon 18, amino acids approximately 1150–1515, were associated in Zhang et al. with GPS in 60%, SBBYSS in 19%, and an intermediate phenotype in 19%. More distal variants—particularly beyond codon 1520—more often produce SBBYSS, while variants around codons 1208–1321 frequently produce GPS/intermediate disease. Genotype alone cannot reliably assign phenotype. (maglione2025phenotypiccharacterizationof pages 9-9, zhang2020furtherdelineationof pages 7-8)

Illustrative variants include c.4943C>G, p.Ser1648Ter, identified de novo by WES, and c.5206C>T, p.Gln1736Ter, a de novo exon-18 nonsense variant in a neonate with hypothyroidism, ASD, hearing loss, genital anomalies, and classic facies. (lundsgaard2017denovokat6b pages 1-2, shin2021aneonatewith pages 1-3)

Modifier genes and chromosomal abnormalities

No validated clinical modifier gene or founder allele is known. Whole-gene deletions or larger copy-number changes may cause KAT6B haploinsufficiency, but classic SBBYSS is usually due to an intragenic sequence variant. Conventional karyotype and chromosomal microarray can therefore be normal. (shin2021aneonatewith pages 1-3, magdalena2023clinicalheterogeneityof pages 1-2)

Epigenetic information

A KAT6A/KAT6B peripheral-blood DNA-methylation episignature was reported in 2023 and may help classify uncertain variants. It is a downstream biomarker of chromatin-regulator dysfunction, not the inherited causal alteration itself. Disease-specific sensitivity and specificity should be taken directly from the primary assay publication before clinical implementation; those metrics were not available in the retrievable text. (maglione2025phenotypiccharacterizationof pages 10-11, maglione2025phenotypiccharacterizationof pages 9-9)

5. Environmental information

No toxin, radiation exposure, diet, smoking, alcohol, exercise pattern, occupational exposure, or infectious agent is established as causal. SBBYSS is not contagious and has no zoonotic component. Environmental factors may influence ordinary health and complications—nutrition affects growth, infections can be more consequential in medically fragile children, and teratogenic valproate exposure is itself hazardous during pregnancy—but they do not explain the Mendelian syndrome.

6. Mechanism and pathophysiology

Upstream causal chain

Pathogenic KAT6B allele → reduced or abnormal KAT6B protein → deficient chromatin acetyltransferase activity and altered recruitment of the BRPF1–ING5/ING4–MEAF6 complex → reduced acetylation at developmentally important chromatin and abnormal gene expression → impaired neural progenitor proliferation/differentiation and disturbed craniofacial, skeletal, cardiac, genital, renal, thyroid and other organogenesis → congenital anomalies plus lifelong neurodevelopmental disability. (bergamasco2024increasinghistoneacetylation pages 1-2, zhang2020furtherdelineationof pages 1-2, zu2022brpf1kat6akat6bcomplexmolecular pages 4-6)

KAT6B transfers acetyl groups from acetyl-CoA to lysines on histones. Reported substrates vary by assay and cell type: H3K14 was emphasized in earlier work, H3K23 in cancer-cell contexts, and the 2024 SBBYSS models showed reduced H3K9 acetylation. Cell-free assays also demonstrate activity toward H1, H2A, H2B, H3 and H4. Thus, “global histone hypoacetylation” is too broad; H3K9ac reduction currently has the strongest direct SBBYSS-model evidence. (bergamasco2024increasinghistoneacetylation pages 1-2, zhang2020furtherdelineationof pages 1-2)

Neural cellular mechanism

KAT6B is highly expressed in embryonic brain and the adult subventricular zone. Deficiency reduces ventricular-zone proliferation, cortical-plate size, layer-V pyramidal neurons and cortical interneurons; adult neural stem cells are fewer and show impaired self-renewal and neuronal differentiation. These upstream defects provide a coherent route to developmental delay, intellectual disability, altered social behavior, hypotonia, and structural brain anomalies. (bergamasco2024increasinghistoneacetylation pages 1-2, lundsgaard2017denovokat6b pages 1-2, zu2022brpf1kat6akat6bcomplexmolecular pages 4-6)

Suggested ontology annotations

GO biological process: histone acetylation; chromatin organization; regulation of transcription by RNA polymerase II; neural stem-cell proliferation; neurogenesis; neuron differentiation; skeletal-system development; embryonic organ morphogenesis.
GO molecular function: histone acetyltransferase activity; lysine N-acetyltransferase activity; chromatin binding.
GO cellular component: nucleus; nucleoplasm; chromatin; histone acetyltransferase complex.
Cell Ontology: neural stem cell; neural progenitor cell; cortical neuron; pyramidal neuron; cortical interneuron; chondrocyte; osteoblast; cardiac progenitor cell. Direct disease evidence is strongest for neural stem/progenitor cells and cortical neurons.

Metabolism, immunity, and tissue injury

No primary enzyme deficiency, storage product, metabolomic/lipidomic signature, autoimmunity, inflammatory cascade, fibrosis, ischemia, or necrosis defines SBBYSS. Acetyl-CoA is the biochemical donor for KAT6B, and the 2024 study observed gene-expression changes involving mitochondrial and neurodegeneration-associated pathways, but did not establish a primary mitochondrial disorder. Immune abnormalities have not been systematically characterized.

Molecular profiling and advanced technologies

Patient-derived/CRISPR-engineered human cells and embryonic cortical-neuron RNA-seq demonstrate reduced H3K9ac and altered transcription that can be partly normalized by valproic acid or acetyl-L-carnitine. No disease-defining single-cell atlas, spatial transcriptomic map, proteomic signature, metabolomic panel, or lipidomic biomarker is yet established for SBBYSS. (bergamasco2024increasinghistoneacetylation pages 15-17, bergamasco2024increasinghistoneacetylation pages 1-2)

7. Anatomical structures affected

SBBYSS is multisystemic:

Primary systems: central nervous system, craniofacial structures/eyelids, skeleton and joints, digits, heart, genital tract, endocrine thyroid, eye and auditory system.
Variable secondary systems: kidneys/urinary tract, gastrointestinal tract, palate/airway, dentition, spine and respiratory system.
Key UBERON suggestions: brain (UBERON:0000955), cerebral cortex, corpus callosum, eyelid, optic nerve, patella, thumb, great toe, heart, kidney, thyroid gland, testis, uterus, palate and larynx.
Subcellular site: nucleus/chromatin and the histone acetyltransferase complex.
Laterality: most dysmorphic and skeletal traits are bilateral; individual hearing, renal, testicular and ocular abnormalities may be unilateral or asymmetric. (zhang2020furtherdelineationof pages 4-5, shin2021aneonatewith pages 1-3)

8. Temporal development

Disease begins prenatally, with occasional increased nuchal translucency/cystic hygroma, growth restriction, polyhydramnios, renal anomalies, or other malformations. The phenotype is usually recognizable congenitally from facial, genital, digital, cardiac, palatal or skeletal findings. Developmental delay, speech impairment and intellectual disability become clearer over infancy and childhood. (maglione2025phenotypiccharacterizationof pages 6-7, zhang2020furtherdelineationof pages 1-2)

There is no validated stage system. The course is chronic and lifelong rather than relapsing-remitting. Congenital structural abnormalities are generally stable unless surgically corrected, whereas consequences such as scoliosis, contractures, feeding problems, thyroid dysfunction, behavioral difficulties and educational needs may evolve. There is no spontaneous molecular remission. Early thyroid replacement, hearing/vision treatment, nutritional support, and developmental therapy represent important windows for preventing avoidable secondary disability.

9. Inheritance and population

Inheritance: autosomal dominant.
Origin: overwhelmingly de novo in reported cases; rare inherited mild alleles show variable expressivity.
Penetrance: likely high for a clinically relevant phenotype, but precise penetrance is unknown and mildly affected carriers may be overlooked.
Expressivity: markedly variable, including within families.
Anticipation: not reported; this is not a repeat-expansion disorder.
Germline mosaicism: biologically possible and relevant to counseling, but no disease-specific rate is established.
Founder effect/carrier frequency: none established; “carrier” is not the usual concept for a dominant disorder.
Consanguinity: not etiologically important.

Prevalence is estimated at <1 per million, but incidence and population-based prevalence have not been measured. No consistent ethnic, geographic, or sex predominance is established. Cases have been reported across multiple ancestries, including European, East Asian, Middle Eastern and African-American individuals. A 2025 review counted 152 molecularly confirmed KAT6B-spectrum patients, illustrating the small and ascertainment-biased evidence base. (maglione2025phenotypiccharacterizationof pages 6-7, maglione2025phenotypiccharacterizationof pages 2-2, davarnia2024denovokat6b pages 1-2)

10. Diagnostics

Clinical recognition

Clinical suspicion should arise from developmental delay/hypotonia plus blepharophimosis or ptosis, mask-like facies, long thumbs/great toes, patellar abnormalities, genital anomalies, congenital heart disease, thyroid disease, hearing loss or lacrimal-duct abnormalities. As Lundsgaard et al. stated in the abstract, “If a patient is suspected of having a blepharophimosis syndrome or SBBYSS, we recommend sequencing the KAT6B gene.” (lundsgaard2017denovokat6b pages 1-2)

Molecular testing strategy

First line: trio exome/genome sequencing or a comprehensive developmental-disorder/blepharophimosis panel including KAT6B.
Phenotype strongly suggestive: full KAT6B sequencing with coverage of all coding exons and splice junctions, not only exon 18.
If sequencing is negative: deletion/duplication analysis or genome sequencing for CNVs and difficult intronic/structural variants.
Parental testing: establish de novo status, identify mildly affected parents, and refine recurrence counseling.
VUS: integrate phenotype, segregation, population frequency, predicted NMD, RNA studies where feasible, and potentially a validated blood DNA-methylation episignature.
CMA/karyotype: useful in the general evaluation of multiple anomalies but may be normal in SBBYSS. FISH, mitochondrial DNA analysis, and repeat-expansion testing are not routine disease-specific tests. (maglione2025phenotypiccharacterizationof pages 9-9, lundsgaard2017denovokat6b pages 1-2, shin2021aneonatewith pages 1-3)

Baseline clinical evaluation

Recommended evaluations include growth and developmental assessment; brain MRI and seizure review; ophthalmology; audiology; echocardiography; renal ultrasound; thyroid function; feeding/swallow and airway assessment; genital/endocrine evaluation; orthopedic examination including patellae, hips, knees and spine; and assessment for cleft palate, dental disease and intestinal malrotation when clinically indicated. Zhang et al. specifically recommended MRI/neurological evaluation, seizure surveillance, ophthalmology, periodic hearing tests, thyroid testing, echocardiography, and renal ultrasonography. (zhang2020furtherdelineationof pages 7-8)

Differential diagnosis

Important alternatives are GPS and intermediate KAT6B disease, KAT6A/Arboleda–Tham syndrome, MED12-related Ohdo syndrome, blepharophimosis-ptosis-epicanthus inversus syndrome due to FOXL2, Kabuki syndrome, Coffin–Siris spectrum, Bohring–Opitz syndrome, Toriello–Carey syndrome, and other chromatinopathies. Patellar/genital anomalies favor KAT6B disease; long thumbs/great toes and mask-like blepharophimosis favor SBBYSS. Molecular testing is necessary because clinical overlap is substantial. (zhang2020furtherdelineationof pages 1-2, zhang2020furtherdelineationof pages 7-8)

Screening

SBBYSS is not included in routine newborn screening. Population carrier screening is inappropriate for a predominantly de novo dominant disorder. Targeted prenatal or preimplantation testing becomes possible once the familial variant is known.

11. Outcome and prognosis

No reliable 5- or 10-year survival estimates, life-expectancy curves, mortality rates, or validated prognostic biomarkers exist. Many individuals survive into adolescence or adulthood, but severity spans mild familial disease to lethal neonatal/infant complications. In the Zhang cohort, three children with GPS died in infancy—from pulmonary hypoplasia secondary to renal hypoplasia/dysplasia, extreme prematurity with multiorgan complications, and influenza H1N1 infection. These deaths should not be extrapolated as a SBBYSS mortality rate. (zhang2020furtherdelineationof pages 7-8)

Long-term morbidity is driven by intellectual/developmental disability, limited speech, behavioral disorders, hearing/vision impairment, feeding problems, hypotonia, mobility-limiting skeletal disease, hypothyroidism, and congenital cardiac/renal disease. Recovery from the genetic disorder is not expected, but treatable complications and functional abilities can improve substantially with early intervention. Prognosis is most influenced by cardiac, renal, respiratory and CNS severity, feeding safety, hearing/vision status, thyroid treatment, and access to developmental support.

12. Treatment

Current standard care

There is no approved disease-modifying therapy. Treatment is individualized and multidisciplinary:

Development: early-intervention services, special education, speech/language therapy, augmentative communication, occupational therapy, and physical therapy.
Feeding: nutritional monitoring, feeding therapy, swallow evaluation, reflux treatment, and enteral support when necessary.
Endocrine: levothyroxine for hypothyroidism; assessment/treatment of hypogonadism or delayed puberty.
Cardiac: standard medical or surgical management of congenital heart disease and arrhythmia; one reported infant underwent ASD patch closure at nine months.
Hearing/vision: hearing aids or other audiological intervention, correction of refractive error/strabismus/ptosis, and lacrimal-duct procedures where indicated.
Orthopedic: physiotherapy, mobility aids, surveillance for scoliosis and contractures, and orthopedic surgery when functionally necessary.
Neurologic/behavioral: standard antiseizure medication if seizures occur and individualized behavioral/psychiatric care.
Genitourinary/palatal/GI: orchiopexy, hypospadias or palate repair, renal/urological treatment, and urgent evaluation of symptoms suggesting malrotation/volvulus. (zhang2020furtherdelineationof pages 7-8, shin2021aneonatewith pages 1-3, davarnia2024denovokat6b pages 1-2)

Suggested MAXO annotations: genetic counseling; exome sequencing; sequence analysis of KAT6B; brain MRI; echocardiography; renal ultrasonography; thyroid-function testing; hearing evaluation; ophthalmologic examination; developmental assessment; physical therapy; occupational therapy; speech therapy; feeding therapy; thyroid-hormone replacement; surgical correction of congenital heart defect; orchiopexy; orthopedic surveillance.

Experimental therapy

The strongest translational development is Bergamasco et al., published 1 April 2024 in Journal of Clinical Investigation (DOI: https://doi.org/10.1172/JCI167672). Their abstract states: “Both compounds improved sociability in Kat6b+/– mice, and ALCAR treatment restored learning and memory.” Valproic acid, an HDAC inhibitor, and acetyl-L-carnitine, an acetyl donor, increased histone acetylation in mutant human cells and mouse brain/blood, partly normalized cortical-neuron transcription, and improved selected behaviors. (bergamasco2024increasinghistoneacetylation pages 15-17, bergamasco2024increasinghistoneacetylation pages 1-2)

This is preclinical evidence only. Valproate can impair cognition in some settings and is a major human teratogen; neither valproate nor acetyl-L-carnitine should be considered an established SBBYSS therapy. No relevant disease-specific interventional clinical trial or NCT identifier was identified in the registry search. Gene replacement, CRISPR, ASO/siRNA, mRNA, cell therapy, immunotherapy, and genotype-guided pharmacotherapy remain unavailable.

13. Prevention

Primary prevention by lifestyle, vaccination, or environmental avoidance is not possible. Prevention is principally reproductive and complication-focused:

Genetic counseling: explain autosomal-dominant inheritance, predominantly de novo occurrence, variable expressivity, and residual recurrence risk from parental germline mosaicism.
Parental testing: essential before assigning a low recurrence risk.
Reproductive options: targeted prenatal diagnosis by chorionic-villus sampling/amniocentesis and preimplantation genetic testing for monogenic disease when the familial variant is known.
Secondary/tertiary prevention: newborn recognition, prompt thyroid treatment, hearing and vision correction, safe feeding, cardiac/renal surveillance, vaccination and ordinary infection prevention, developmental therapies, and monitoring for orthopedic and GI complications.

There is no vaccine, chemoprophylaxis, public-health environmental intervention, or population screening program specific to SBBYSS.

14. Other species and natural disease

No well-established naturally occurring veterinary analogue of SBBYSS was identified, and the disorder has no zoonotic potential. The relevant comparative species is the laboratory mouse, Mus musculus (NCBI Taxonomy 10090), whose ortholog is Kat6b (Querkopf/Qkf). KAT6B developmental functions are evolutionarily conserved, particularly in neural stem/progenitor biology, cortical development and skeletogenesis. Naturally occurring breed-specific disease, VBO mapping and cross-species transmission are not applicable.

15. Model organisms and experimental systems

Mouse models

Kat6b heterozygous mice provide the most disease-relevant model. They show approximately 50% cortical Kat6b transcript reduction and deficits in learning, memory and social behavior. Homozygous deficiency produces underdeveloped jaws and frontal bones, delayed neonatal respiratory adaptation and death before weaning. Earlier models also showed reduced cortical progenitor proliferation, cortical-plate hypoplasia, reduced pyramidal neurons/interneurons, and impaired adult neural-stem-cell maintenance. These models recapitulate neurodevelopmental, craniofacial and behavioral aspects but do not reproduce every human congenital feature or the full allelic complexity of NMD-escaping truncations. (bergamasco2024increasinghistoneacetylation pages 1-2, zu2022brpf1kat6akat6bcomplexmolecular pages 4-6)

Human cellular models

CRISPR-engineered HEK293T clones carrying SBBYSS-specific KAT6B variants and primary/cultured cortical-neuron systems demonstrated reduced KAT6B expression, reduced H3K9ac and altered gene expression. Their key strength is allele-specific molecular testing; limitations include non-developmental cell context for HEK293T cells and inability to model whole-organ morphogenesis. (bergamasco2024increasinghistoneacetylation pages 1-2)

No validated SBBYSS patient iPSC, cerebral-organoid, zebrafish, Drosophila, C. elegans, or naturally diseased animal model was established in the retrieved evidence. Future priorities include patient-derived neural and mesenchymal iPSCs, allele-specific knock-in models, single-cell developmental atlases, and direct functional comparison of NMD-sensitive versus NMD-escaping variants.

Recent developments and expert interpretation

Spectrum rather than rigid syndromes: the 2023 Polish cohort documented six molecularly confirmed patients with shared facial/developmental findings but variable and sometimes mild knee disease. Its conclusion—that phenotypic differences support a broader spectrum—is consistent with the 32-person allelic-series study. (zhang2020furtherdelineationof pages 1-2, magdalena2023clinicalheterogeneityof pages 1-2)
Epigenomic diagnosis: 2023 KAT6A/KAT6B methylation work introduced a potentially useful functional biomarker for VUS resolution, although primary performance metrics require verification before clinical deployment. (maglione2025phenotypiccharacterizationof pages 10-11, maglione2025phenotypiccharacterizationof pages 9-9)
Postnatal reversibility: the 2024 human-cell/mouse study is the first strong proof that at least some downstream acetylation, transcriptional and behavioral abnormalities remain pharmacologically modifiable after birth. It supports therapeutic development, not off-label clinical use. (bergamasco2024increasinghistoneacetylation pages 15-17, bergamasco2024increasinghistoneacetylation pages 1-2)
Continuing phenotype expansion: a 2024 Iranian report added detailed skeletal and white-matter findings, but individual case reports cannot establish frequency or causality for newly observed features. (davarnia2024denovokat6b pages 1-2)

Evidence limitations

The evidence base consists mainly of retrospective cohorts, literature compilations and case reports. Frequencies are vulnerable to referral bias, incomplete phenotyping and changing subtype definitions. There are no population registries, controlled human trials, longitudinal adult cohorts, validated patient-reported outcome measures, or robust penetrance estimates. Mechanistic evidence is strongest for KAT6B deficiency, H3K9 hypoacetylation and neural progenitor dysfunction; dominant-negative effects of terminal truncations remain plausible but not conclusively proven. PMIDs were not present in the retrievable source text and therefore are not invented here; DOI URLs and publication dates are supplied for traceability.

References

(bergamasco2024increasinghistoneacetylation pages 1-2): Maria I. Bergamasco, Hannah K. Vanyai, Alexandra L. Garnham, Niall D. Geoghegan, Adam P. Vogel, Samantha Eccles, Kelly L. Rogers, Gordon K. Smyth, Marnie E. Blewitt, Anthony J. Hannan, Tim Thomas, and Anne K. Voss. Increasing histone acetylation improves sociability and restores learning and memory in kat6b-haploinsufficient mice. The Journal of Clinical Investigation, Apr 2024. URL: https://doi.org/10.1172/jci167672, doi:10.1172/jci167672. This article has 21 citations.
(zhang2020furtherdelineationof pages 1-2): Li Xin Zhang, Gabrielle Lemire, Claudia Gonzaga-Jauregui, Sirinart Molidperee, Carolina Galaz-Montoya, David S. Liu, Alain Verloes, Amelle G. Shillington, Kosuke Izumi, Alyssa L. Ritter, Beth Keena, Elaine Zackai, Dong Li, Elizabeth Bhoj, Jennifer M. Tarpinian, Emma Bedoukian, Mary K. Kukolich, A. Micheil Innes, Grace U. Ediae, Sarah L. Sawyer, Karippoth Mohandas Nair, Para Chottil Soumya, Kinattinkara R. Subbaraman, Frank J. Probst, Jennifer A. Bassetti, Reid V. Sutton, Richard A. Gibbs, Chester Brown, Philip M. Boone, Ingrid A. Holm, Marco Tartaglia, Giovanni Battista Ferrero, Marcello Niceta, Maria Lisa Dentici, Francesca Clementina Radio, Boris Keren, Constance F. Wells, Christine Coubes, Annie Laquerrière, Jacqueline Aziza, Charlotte Dubucs, Sheela Nampoothiri, David Mowat, Millan S. Patel, Ana Bracho, Francisco Cammarata-Scalisi, Alper Gezdirici, Alberto Fernandez-Jaen, Natalie Hauser, Yuri A. Zarate, Katherine A. Bosanko, Klaus Dieterich, John C. Carey, Jessica X. Chong, Deborah A. Nickerson, Michael J. Bamshad, Brendan H. Lee, Xiang-Jiao Yang, James R. Lupski, and Philippe M. Campeau. Further delineation of the clinical spectrum of kat6b disorders and allelic series of pathogenic variants. Genetics in Medicine, 22:1338-1347, Aug 2020. URL: https://doi.org/10.1038/s41436-020-0811-8, doi:10.1038/s41436-020-0811-8. This article has 64 citations and is from a highest quality peer-reviewed journal.
(magdalena2023clinicalheterogeneityof pages 1-2): Klaniewska Magdalena, Bolanowska‐Tyszko Anna, Latos‐Bielenska Anna, Jezela‐Stanek Aleksandra, Szczaluba Krzysztof, Krajewska‐Walasek Malgorzata, Ciara Elzbieta, Pelc Magdalena, Jurkiewicz Dorota, Stawinski Piotr, Zubkiewicz‐Kucharska Agnieszka, Rydzanicz Małgorzata, Ploski Rafal, and Smigiel Robert. Clinical heterogeneity of polish patients with kat6b–related disorder. Molecular Genetics & Genomic Medicine, Sep 2023. URL: https://doi.org/10.1002/mgg3.2265, doi:10.1002/mgg3.2265. This article has 6 citations and is from a peer-reviewed journal.
(shin2021aneonatewith pages 1-3): Ji Hye Shin, Han Hyuk Lim, Mi Hyeon Gang, Seon Young Kim, Shin-seung Yang, and Mea-young Chang. A neonate with say–barber–biesecker–young–simpson syndrome with a novel pathogenic mutation in kat6b gene: a case report. Journal of Genetic Medicine, 18:147-151, Dec 2021. URL: https://doi.org/10.5734/jgm.2021.18.2.147, doi:10.5734/jgm.2021.18.2.147. This article has 2 citations.
(maglione2025phenotypiccharacterizationof pages 6-7): Vittorio Maglione, Antonio Pizzuti, Gioia Mastromoro, Eleonora Cresta, Paola Favata, Maria Cristina Digilio, Rossella Capolino, Maria Lisa Dentici, Lorenzo Sinibaldi, Antonio Novelli, Marco Tartaglia, Gianluca Terrin, and Viviana Cardilli. Phenotypic characterization of seven pediatric patients diagnosed with kat6b-related disorders: case series and review of the literature. American journal of medical genetics. Part A, pages e64100, Apr 2025. URL: https://doi.org/10.1002/ajmg.a.64100, doi:10.1002/ajmg.a.64100. This article has 1 citations and is from a peer-reviewed journal.
(maglione2025phenotypiccharacterizationof pages 2-2): Vittorio Maglione, Antonio Pizzuti, Gioia Mastromoro, Eleonora Cresta, Paola Favata, Maria Cristina Digilio, Rossella Capolino, Maria Lisa Dentici, Lorenzo Sinibaldi, Antonio Novelli, Marco Tartaglia, Gianluca Terrin, and Viviana Cardilli. Phenotypic characterization of seven pediatric patients diagnosed with kat6b-related disorders: case series and review of the literature. American journal of medical genetics. Part A, pages e64100, Apr 2025. URL: https://doi.org/10.1002/ajmg.a.64100, doi:10.1002/ajmg.a.64100. This article has 1 citations and is from a peer-reviewed journal.
(zhang2020furtherdelineationof pages 7-8): Li Xin Zhang, Gabrielle Lemire, Claudia Gonzaga-Jauregui, Sirinart Molidperee, Carolina Galaz-Montoya, David S. Liu, Alain Verloes, Amelle G. Shillington, Kosuke Izumi, Alyssa L. Ritter, Beth Keena, Elaine Zackai, Dong Li, Elizabeth Bhoj, Jennifer M. Tarpinian, Emma Bedoukian, Mary K. Kukolich, A. Micheil Innes, Grace U. Ediae, Sarah L. Sawyer, Karippoth Mohandas Nair, Para Chottil Soumya, Kinattinkara R. Subbaraman, Frank J. Probst, Jennifer A. Bassetti, Reid V. Sutton, Richard A. Gibbs, Chester Brown, Philip M. Boone, Ingrid A. Holm, Marco Tartaglia, Giovanni Battista Ferrero, Marcello Niceta, Maria Lisa Dentici, Francesca Clementina Radio, Boris Keren, Constance F. Wells, Christine Coubes, Annie Laquerrière, Jacqueline Aziza, Charlotte Dubucs, Sheela Nampoothiri, David Mowat, Millan S. Patel, Ana Bracho, Francisco Cammarata-Scalisi, Alper Gezdirici, Alberto Fernandez-Jaen, Natalie Hauser, Yuri A. Zarate, Katherine A. Bosanko, Klaus Dieterich, John C. Carey, Jessica X. Chong, Deborah A. Nickerson, Michael J. Bamshad, Brendan H. Lee, Xiang-Jiao Yang, James R. Lupski, and Philippe M. Campeau. Further delineation of the clinical spectrum of kat6b disorders and allelic series of pathogenic variants. Genetics in Medicine, 22:1338-1347, Aug 2020. URL: https://doi.org/10.1038/s41436-020-0811-8, doi:10.1038/s41436-020-0811-8. This article has 64 citations and is from a highest quality peer-reviewed journal.
(davarnia2024denovokat6b pages 1-2): Behzad Davarnia, Mohammad Panahi, Bahareh Rahimi, Hassan Anari, Reza Farajollahi, Ehsan Abbaspour Rodbaneh, and Farhad Jeddi. De novo kat6b mutation causes say–barber–biesecker–young–simpson variant of ohdo syndrome in an iranian boy: a case report. Journal of Medical Case Reports, Jan 2024. URL: https://doi.org/10.1186/s13256-023-04237-w, doi:10.1186/s13256-023-04237-w. This article has 7 citations and is from a peer-reviewed journal.
(lundsgaard2017denovokat6b pages 1-2): Malene Lundsgaard, Vang Q. Le, Anja Ernst, Hans C. Laugaard-Jacobsen, Kirsten Rasmussen, Inge S. Pedersen, and Michael B. Petersen. De novo kat6b mutation identified with whole-exome sequencing in a girl with say-barber/biesecker/young-simpson syndrome. Molecular Syndromology, 8:24-29, Nov 2017. URL: https://doi.org/10.1159/000452258, doi:10.1159/000452258. This article has 12 citations and is from a peer-reviewed journal.
(zhang2020furtherdelineationof pages 4-5): Li Xin Zhang, Gabrielle Lemire, Claudia Gonzaga-Jauregui, Sirinart Molidperee, Carolina Galaz-Montoya, David S. Liu, Alain Verloes, Amelle G. Shillington, Kosuke Izumi, Alyssa L. Ritter, Beth Keena, Elaine Zackai, Dong Li, Elizabeth Bhoj, Jennifer M. Tarpinian, Emma Bedoukian, Mary K. Kukolich, A. Micheil Innes, Grace U. Ediae, Sarah L. Sawyer, Karippoth Mohandas Nair, Para Chottil Soumya, Kinattinkara R. Subbaraman, Frank J. Probst, Jennifer A. Bassetti, Reid V. Sutton, Richard A. Gibbs, Chester Brown, Philip M. Boone, Ingrid A. Holm, Marco Tartaglia, Giovanni Battista Ferrero, Marcello Niceta, Maria Lisa Dentici, Francesca Clementina Radio, Boris Keren, Constance F. Wells, Christine Coubes, Annie Laquerrière, Jacqueline Aziza, Charlotte Dubucs, Sheela Nampoothiri, David Mowat, Millan S. Patel, Ana Bracho, Francisco Cammarata-Scalisi, Alper Gezdirici, Alberto Fernandez-Jaen, Natalie Hauser, Yuri A. Zarate, Katherine A. Bosanko, Klaus Dieterich, John C. Carey, Jessica X. Chong, Deborah A. Nickerson, Michael J. Bamshad, Brendan H. Lee, Xiang-Jiao Yang, James R. Lupski, and Philippe M. Campeau. Further delineation of the clinical spectrum of kat6b disorders and allelic series of pathogenic variants. Genetics in Medicine, 22:1338-1347, Aug 2020. URL: https://doi.org/10.1038/s41436-020-0811-8, doi:10.1038/s41436-020-0811-8. This article has 64 citations and is from a highest quality peer-reviewed journal.
(zu2022brpf1kat6akat6bcomplexmolecular pages 4-6): Gaoyu Zu, Ying Liu, Jingli Cao, Baicheng Zhao, Hang Zhang, and Linya You. Brpf1-kat6a/kat6b complex: molecular structure, biological function and human disease. Cancers, 14:4068, Aug 2022. URL: https://doi.org/10.3390/cancers14174068, doi:10.3390/cancers14174068. This article has 35 citations.
(magdalena2023clinicalheterogeneityof pages 10-10): Klaniewska Magdalena, Bolanowska‐Tyszko Anna, Latos‐Bielenska Anna, Jezela‐Stanek Aleksandra, Szczaluba Krzysztof, Krajewska‐Walasek Malgorzata, Ciara Elzbieta, Pelc Magdalena, Jurkiewicz Dorota, Stawinski Piotr, Zubkiewicz‐Kucharska Agnieszka, Rydzanicz Małgorzata, Ploski Rafal, and Smigiel Robert. Clinical heterogeneity of polish patients with kat6b–related disorder. Molecular Genetics & Genomic Medicine, Sep 2023. URL: https://doi.org/10.1002/mgg3.2265, doi:10.1002/mgg3.2265. This article has 6 citations and is from a peer-reviewed journal.
(bergamasco2024increasinghistoneacetylation pages 15-17): Maria I. Bergamasco, Hannah K. Vanyai, Alexandra L. Garnham, Niall D. Geoghegan, Adam P. Vogel, Samantha Eccles, Kelly L. Rogers, Gordon K. Smyth, Marnie E. Blewitt, Anthony J. Hannan, Tim Thomas, and Anne K. Voss. Increasing histone acetylation improves sociability and restores learning and memory in kat6b-haploinsufficient mice. The Journal of Clinical Investigation, Apr 2024. URL: https://doi.org/10.1172/jci167672, doi:10.1172/jci167672. This article has 21 citations.
(maglione2025phenotypiccharacterizationof pages 9-9): Vittorio Maglione, Antonio Pizzuti, Gioia Mastromoro, Eleonora Cresta, Paola Favata, Maria Cristina Digilio, Rossella Capolino, Maria Lisa Dentici, Lorenzo Sinibaldi, Antonio Novelli, Marco Tartaglia, Gianluca Terrin, and Viviana Cardilli. Phenotypic characterization of seven pediatric patients diagnosed with kat6b-related disorders: case series and review of the literature. American journal of medical genetics. Part A, pages e64100, Apr 2025. URL: https://doi.org/10.1002/ajmg.a.64100, doi:10.1002/ajmg.a.64100. This article has 1 citations and is from a peer-reviewed journal.
(maglione2025phenotypiccharacterizationof pages 10-11): Vittorio Maglione, Antonio Pizzuti, Gioia Mastromoro, Eleonora Cresta, Paola Favata, Maria Cristina Digilio, Rossella Capolino, Maria Lisa Dentici, Lorenzo Sinibaldi, Antonio Novelli, Marco Tartaglia, Gianluca Terrin, and Viviana Cardilli. Phenotypic characterization of seven pediatric patients diagnosed with kat6b-related disorders: case series and review of the literature. American journal of medical genetics. Part A, pages e64100, Apr 2025. URL: https://doi.org/10.1002/ajmg.a.64100, doi:10.1002/ajmg.a.64100. This article has 1 citations and is from a peer-reviewed journal.

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Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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Say–Barber–Biesecker–Young–Simpson syndrome: disease-characteristics report

Executive summary

1. Disease information

Definition and classification

2. Etiology, risk, and protective factors

Causal factor

Risk factors

Protective factors and gene–environment interaction

3. Phenotypes

Core phenotype map

Functional and quality-of-life effects

4. Genetic and molecular information

Causal gene

Variant architecture and consequence

Modifier genes and chromosomal abnormalities

Epigenetic information

5. Environmental information

6. Mechanism and pathophysiology

Upstream causal chain

Neural cellular mechanism

Metabolism, immunity, and tissue injury

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical recognition

Molecular testing strategy

Baseline clinical evaluation

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

Current standard care

Experimental therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse models

Human cellular models

Recent developments and expert interpretation

Evidence limitations

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