Developmental Delay, Hypotonia, Musculoskeletal Defects, and Behavioral Abnormalities

Executive Summary

DEHMBA is a recently delineated (2021), autosomal dominant, early-onset neurodevelopmental disorder caused by de novo heterozygous truncating (and occasionally other loss-of-function) variants in SRCAP (SNF2-related CREBBP activator protein), the same gene that — when truncated within a specific "hotspot" (exons 33–34) — causes the clinically distinct Floating-Harbor syndrome (FLHS). DEHMBA is characterized by global developmental delay/intellectual disability, speech delay, hypotonia, behavioral/psychiatric abnormalities (including autism spectrum features in roughly half of patients), and variable, non-diagnostic musculoskeletal and facial features. It is genotypically and epigenetically distinguishable from FLHS by variant location and a distinct genome-wide DNA methylation ("episignature") profile.

1. Disease Information

Overview: DEHMBA (also styled "SRCAP-related neurodevelopmental disorder," non-FLHS-locus type) is an early-onset, autosomal dominant neurodevelopmental disorder first delineated by Rots et al. (2021), who reported 33 unrelated individuals with de novo heterozygous truncating SRCAP variants that mapped either proximal (n=28) or distal (n=5) to the FLHS mutational hotspot in exons 33–34. Affected individuals share global developmental delay (with or without intellectual disability), speech/language delay, hypotonia, behavioral/psychiatric problems, non-specific facial dysmorphism, and variable musculoskeletal findings, but they conspicuously lack the short stature, brachydactyly, delayed bone age, and characteristic gestalt facies that define FLHS — the original disorder associated with SRCAP.

Key identifiers: - OMIM: #619595 — "DEVELOPMENTAL DELAY, HYPOTONIA, MUSCULOSKELETAL DEFECTS, AND BEHAVIORAL ABNORMALITIES; DEHMBA" OMIM entry - Gene locus (OMIM): 611421 — SRCAP (SNF2-related CBP activator protein) OMIM gene entry - MONDO: MONDO:0859202 - MedGen: UID 1794222 / Concept ID C5562012 MedGen - Gene: SRCAP, chromosome 16p11.2 (GRCh38 ~16:30,698,209–30,741,409) - Inheritance: Autosomal dominant, typically de novo - Related/allelic disorder: Floating-Harbor syndrome (OMIM #136140), caused by truncating variants restricted to exons 33–34 of the same gene - Also allelic to: an emerging developmental and epileptic encephalopathy (DEE) phenotype (Liang et al., 2026, Epilepsia) associated with more severely damaging de novo SRCAP* variants (truncating or damaging missense) — see Section 6/8 below

Synonyms: DEHMBA; SRCAP-related neurodevelopmental disorder (non-Floating-Harbor); "developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities syndrome"

Data provenance: The disease was delineated from an aggregated, multi-institution research cohort (international collaborative case series compiled via GeneMatcher-type networks and clinical/research exome sequencing), not from a single EHR-based population — i.e., this is a rare-disease gene-discovery cohort of 33+ individuals rather than an aggregated administrative/claims dataset.

2. Etiology

Disease causal factor: DEHMBA is caused by de novo heterozygous truncating variants in SRCAP (nonsense, frameshift, canonical splice-site) located outside (proximal or distal to) the FLHS exon 33–34 hotspot. A subsequent report (Yamamoto et al., 2024, J Hum Genet) identified a de novo intronic SRCAP variant detected only by combined exome plus whole-transcriptome sequencing, causing DEHMBA with a severe sleep disorder — illustrating that some causal variants are missed by exome sequencing alone and require RNA-level confirmation of aberrant splicing. A separate case report (2022) described a de novo SVA retrotransposon insertion in exon 13 of SRCAP producing a DEHMBA-like neurodevelopmental phenotype, expanding the mutational mechanism spectrum beyond simple SNVs/indels.

Genetic risk factors: - All reported pathogenic variants are truncating, splice-altering, or structural (retrotransposon insertion) loss-of-function-type changes in SRCAP, essentially all occurring de novo (not inherited from unaffected parents). - Nonsense-mediated decay (NMD) location relative to the FLHS hotspot appears to determine phenotype: truncations proximal or distal to exons 33–34 → DEHMBA; truncations restricted to exons 33–34 (escaping NMD, producing a stable truncated protein retaining an N-terminal ATPase/helicase domain) → FLHS. This is the accepted allelic mechanism model. - A 16p11.2 microdeletion encompassing SRCAP has separately been reported in a patient with speech impairment, global developmental delay, and behavioral problems — indicating haploinsufficiency of SRCAP (rather than a specific truncated-protein dominant-negative/gain-of-function effect) is sufficient to produce a DEHMBA-like phenotype, consistent with the loss-of-function/haploinsufficiency model. - SRCAP is independently recognized as a high-confidence autism spectrum disorder (ASD) risk gene: de novo loss-of-function variants were identified in ASD probands in the Simons Simplex Collection (Iossifov et al. 2014) and The Autism Simplex Collection (Stessman et al. 2017), predating and converging with the DEHMBA delineation.

Environmental risk factors: None established; DEHMBA is a purely monogenic disorder with no reported environmental, infectious, or lifestyle contributory factors.

Protective factors: None reported in the literature to date.

Gene-environment interactions: Not studied/reported for this ultra-rare, recently described disorder.

3. Phenotypes

Frequencies below reflect the Rots et al. (2021) cohort (n=33, unless noted) and subsequent case reports; percentages should be treated as approximate given cohort size.

Neurodevelopmental / cognitive: - Global developmental delay — core, essentially universal feature. HP:0001263 - Mild to severe intellectual disability (variable severity across the cohort). HP:0001249 - Speech and language delay, often disproportionately affected. HP:0000750 - Progression: generally stable, non-regressive developmental impairment rather than a degenerative course (consistent with a chromatin-remodeling neurodevelopmental disorder), though the sleep-disorder case report noted an unusually severe secondary sleep phenotype.

Behavioral / psychiatric (a defining, name-bearing category): - Autism spectrum disorder / autistic features — reported in roughly half of patients. HP:0000717 - Challenging/disruptive behavior, anger. HP:0000708 (Aggressive behavior) - Anxiety. HP:0000739 - ADHD / attention-deficit/hyperactivity disorder. HP:0007018 - Tics / Tourette syndrome — reported in a subset (4 of 33). HP:0100033 / HP:0100022 - Psychosis — reported in a subset (4 of 33). HP:0000709

Neurological: - Hypotonia — core, name-bearing feature, generally axial/central. HP:0001252 - Seizures — reported in a minority (~3 of 33, ~9%). HP:0001250 - Severe sleep disturbance highlighted as a prominent feature in at least one intronic-variant case (Yamamoto et al. 2024). HP:0002360

Musculoskeletal (a defining, name-bearing category — notably variable/non-diagnostic, unlike FLHS): - Joint hypermobility. HP:0001382 - Chronic musculoskeletal pain. HP:0034274 (Chronic pain) / generalized musculoskeletal pain - Scoliosis. HP:0002650 - Pectus deformities (excavatum/carinatum). HP:0000768 - Delayed skeletal maturation (bone age delay), reported in MedGen feature list but not the severe, near-universal delayed bone age characteristic of FLHS. HP:0002750 - Short stature reported in a subset — again notably less consistent/severe than in FLHS, an important differentiator. HP:0004322

Craniofacial (non-specific — explicitly distinguishes DEHMBA from FLHS, which has a highly recognizable gestalt): - Macrocephaly or microcephaly (variable, not unidirectional). HP:0000256 / HP:0000252 - Long face, prominent forehead. HP:0000276 / HP:0011220 - Wide nasal bridge, wide mouth. HP:0000431 / HP:0000154 - Long philtrum. HP:0000343 - Epicanthus, narrow palpebral fissures. HP:0000286 / HP:0045025 - Everted lower lip vermilion, thin upper lip vermilion. HP:0000232 / HP:0000219 - Mandibular prognathia, retrognathia. HP:0000303 / HP:0000278 - Periorbital fullness. HP:0000629 - Protruding ears. HP:0000411

Other systemic/organ features: - Gastroesophageal reflux. HP:0002020 - Cryptorchidism (males). HP:0000028 - Ocular abnormalities: hypermetropia, myopia, strabismus. HP:0000540 / HP:0000545 / HP:0000486

Quality-of-life impact: No disease-specific QoL instrument data have been published given the disorder's recent delineation (2021) and rarity; QoL burden is inferred from the combination of intellectual disability, behavioral/psychiatric comorbidity (anxiety, aggression, psychosis in a subset), and chronic musculoskeletal pain, which together are expected to substantially affect adaptive functioning, education, and family caregiving burden, consistent with other SRCAP-related and chromatinopathy neurodevelopmental disorders.

4. Genetic / Molecular Information

Gene: SRCAP (HGNC:16974; also known as SNF2-related CREBBP activator protein, DOM1, FLHS gene), chromosome 16p11.2.

Causal variant classes: - Truncating variants (nonsense, frameshift) located proximal or distal to the FLHS hotspot (exons 33–34) — the predominant mechanism in the founding Rots et al. 2021 cohort (28 proximal, 5 distal of 33 patients). - Canonical splice-site variants. - Deep intronic variant causing aberrant splicing/pseudoexon inclusion, detectable only via combined exome + whole transcriptome sequencing (Yamamoto et al., 2024, PMID:38448605) — this case underscores a diagnostic-methodology point relevant to curation: standard exome sequencing can produce false-negative results in SRCAP-suspected DEHMBA, and RNA-based confirmation may be required. - Structural variant / retrotransposon insertion: a de novo SVA element insertion in exon 13 of SRCAP produced a DEHMBA-like neurodevelopmental phenotype (2022 case report, PMID:35768521), expanding recognized mutational mechanisms beyond point mutations/indels. - 16p11.2 microdeletion encompassing SRCAP — a contiguous-gene/whole-gene deletion also reported to produce a DEHMBA-like presentation, supporting a haploinsufficiency mechanism.

Variant origin and zygosity: Essentially all reported DEHMBA variants are de novo and heterozygous; the disorder is not described as recessive or biallelic (contrast with the Liang et al. 2026 DEE/focal-epilepsy report, which found biallelic, milder-damage variants in a distinct focal-epilepsy subgroup — see Section 8).

Functional consequence / mechanism: Loss-of-function/haploinsufficiency of SRCAP. Truncating variants proximal or distal to exons 33–34 are presumed to trigger nonsense-mediated decay or otherwise abolish functional SRCAP protein, in contrast to FLHS-causing truncations restricted to exons 33–34, which escape NMD and produce a stable, likely dominant-negative or altered-function truncated protein retaining the N-terminal ATPase/helicase domain but lacking C-terminal regulatory sequence. This variant-position-dependent mechanism (NMD-escape hotspot vs. NMD-triggering elsewhere in the gene) is the accepted molecular explanation for the phenotypic divergence between FLHS and DEHMBA from the same gene.

Epigenetic signature: Rots et al. (2021) demonstrated that DEHMBA-causing (non-hotspot) truncating SRCAP variants produce a distinct, disorder-specific genome-wide DNA methylation ("episignature") profile, separable from the FLHS episignature and from controls, now incorporated into the clinically validated EpiSign DNA methylation array diagnostic platform as one of the growing set (~70+) of chromatinopathy episignatures used to resolve variants of uncertain significance and support diagnosis in genetically unresolved cases.

Population frequency / constraint: SRCAP is a large, evolutionarily conserved gene; independent evidence of strong loss-of-function intolerance comes from its established status as a high-confidence ASD risk gene in large de novo variant burden studies (Iossifov et al. 2014; Stessman et al. 2017), consistent with a highly constrained gene where de novo LoF variants are pathogenic rather than population polymorphisms.

Modifier genes: None specifically established for DEHMBA.

Chromosomal abnormalities: A 16p11.2 microdeletion encompassing SRCAP has been reported with an overlapping phenotype (speech impairment, developmental delay, behavioral problems), distinct from the well-known recurrent 16p11.2 BP4–BP5 CNV syndrome (which is a different, more proximal/larger interval); curators should take care to distinguish SRCAP-specific deletions from the classic 16p11.2 microdeletion/microduplication syndrome.

5. Environmental Information

No environmental, toxin, occupational, dietary, or lifestyle factors are implicated in DEHMBA; it is a purely monogenic, de novo disorder. No infectious triggers are reported. This section is essentially "not applicable" for this Mendelian chromatin-remodeling disorder, analogous to other de novo dominant neurodevelopmental syndromes.

6. Mechanism / Pathophysiology

Causal chain (numbered, from molecular lesion to clinical manifestation):

1. A de novo heterozygous loss-of-function variant (truncating SNV/indel, canonical splice variant, deep intronic splice-altering variant, or retrotransposon insertion) arises in SRCAP, located outside the FLHS exon 33–34 hotspot — leads to production of a non-functional or absent SRCAP protein from one allele (via nonsense-mediated decay or structural disruption).
2. Reduced functional SRCAP dosage (haploinsufficiency) results in impaired assembly/activity of the SRCAP chromatin-remodeling complex (SRCAP, DMAP1, YL1/VPS72, RUVBL1, RUVBL2, ACTL6A, ARP6/ACTR6, ACTIN, GAS41, ZNHIT1), the human ortholog of the yeast SWR1 complex.
3. Impaired SRCAP complex activity leads to deficient ATP-dependent exchange of canonical histone H2A/H2B dimers for histone variant H2A.Z-containing dimers at target nucleosomes (this is the complex's core catalytic function; direct structural biology confirms SRCAP and its paralog TIP60/EP400 as the principal human H2A.Z-depositing remodelers, distinguishing them mechanistically from the related INO80 complex, which removes rather than deposits H2A.Z).
4. Genome-wide mis-deposition of H2A.Z results in dysregulated chromatin accessibility and altered transcriptional output at SRCAP target loci — this step is directly evidenced in humans by the reproducible, disorder-specific genome-wide DNA methylation episignature detected in DEHMBA patients (Rots et al. 2021), a downstream chromatin/epigenomic correlate of SRCAP dysfunction.
5. In model systems, one specific and mechanistically well-characterized downstream consequence is reduced expression of Satb2 (a chromatin-organizing transcription factor itself causal for a distinct neurodevelopmental disorder, SATB2-associated syndrome), shown in Srcap+/- mice to result from diminished H2A.Z occupancy at the Satb2 promoter — this is a mouse/model-organism finding, inferred to be translationally relevant but not yet directly confirmed in human SRCAP-DEHMBA brain tissue (a candidate HUMAN_MODEL_MISMATCH-type gap for KB curation).
6. Reduced Satb2 (and dysregulation of ~27 additional ASD-implicated genes identified by RNA sequencing in the mouse model) leads to downstream neurodevelopmental cellular abnormalities: in Srcap+/- mice, a decreased number of parvalbumin (PV)-expressing interneurons in the retrosplenial cortex and dentate gyrus, and altered dendritic structure, synaptic density, and synaptic transmission in the dentate gyrus.
7. These cellular/circuit-level abnormalities result in the behavioral phenotype observed in the mouse model — impaired social novelty, repetitive/stereotyped behaviors, anxiety-like behavior, and learning/memory deficits — mirroring, at a model-organism level, the human behavioral/psychiatric domain of DEHMBA (autism spectrum features, anxiety, ADHD, aggression).
8. In parallel (branch point), haploinsufficiency-driven chromatin dysregulation during development leads to the human clinical phenotype of global developmental delay, intellectual disability, speech/language delay, and hypotonia — the core neurodevelopmental triad — through mechanisms presumed analogous to (7) but not yet directly dissected in human neural tissue.
9. A separate, less-characterized branch: SRCAP dysfunction also contributes to variable musculoskeletal (joint hypermobility, scoliosis, pectus deformity, delayed bone maturation) and craniofacial dysmorphic features, presumably reflecting a broader developmental role of SRCAP/H2A.Z chromatin regulation in mesenchymal/skeletal lineages, though the specific cell types and pathways involved in this branch have not been mechanistically dissected (a knowledge gap).
10. Rescue evidence supporting the causal chain: AAV-mediated delivery of Satb2 into Srcap+/- mice ameliorated both the cellular abnormalities (interneuron/synaptic deficits) and the behavioral phenotype, providing interventional (not merely correlative) support that the Srcap→H2A.Z→Satb2 axis is mechanistically load-bearing for at least the behavioral/autistic component of the model phenotype.

Molecular pathways: SWR1/SRCAP chromatin-remodeling pathway; H2A.Z histone variant deposition/exchange pathway; downstream transcriptional regulation of neurodevelopmental genes including SATB2. GO terms: GO:0043486 (histone exchange), GO:0031498 (chromatin disassembly), GO:0006338 (chromatin remodeling), GO:0035102 (PRC1/SWI-SNF-type — not directly applicable, more precisely GO:0000812 Swr1 complex).

Cellular processes: Chromatin remodeling; transcriptional regulation; neuronal differentiation and interneuron specification (parvalbumin+ interneuron development); synaptogenesis/synaptic density regulation; dendritic morphogenesis.

Protein dysfunction: Loss of function via truncation/NMD (haploinsufficiency) rather than a stable dominant-negative or gain-of-function product (contrast with the FLHS-causing truncations, which retain the N-terminal ATPase domain and are hypothesized to act via a distinct mechanism producing a different, growth-restriction-dominated phenotype).

Cell types implicated: Excitatory and inhibitory (parvalbumin-expressing GABAergic interneuron; Cell Ontology CL:0000850 or more specifically CL:0002273 for PV+ interneurons) neurons in cortex (retrosplenial cortex) and hippocampal dentate gyrus (granule neurons, CL:0000870), based on mouse model data.

Epigenetic changes: A genome-wide, disorder-specific DNA methylation episignature is the best-established human molecular biomarker of SRCAP-DEHMBA pathophysiology, now used diagnostically via the EpiSign platform.

Molecular profiling: RNA sequencing in the Srcap+/- mouse model identified dysregulation of 27 ASD-associated genes; no published human transcriptomic, proteomic, or single-cell profiling of DEHMBA patient tissue was identified in this search (a gap — most cellular/molecular mechanistic data derive from the mouse model, an important HUMAN_MODEL_MISMATCH consideration for curation given that direct human neural-tissue confirmation of the Satb2/H2A.Z axis is not yet available).

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system (brain — cognition, behavior, tone regulation); musculoskeletal system (joints, spine, chest wall, long bones). - Secondary: Gastrointestinal (reflux); genitourinary (cryptorchidism); ophthalmologic (refractive errors, strabismus); craniofacial skeleton. - Body systems: Nervous system, musculoskeletal system, behavioral/psychiatric domain, digestive system, genitourinary system, sensory (ocular) system.

Tissue/cell level: Neuronal tissue (cortical and hippocampal neurons; parvalbumin-positive GABAergic interneurons per mouse model — Cell Ontology CL:0000850/CL:0002273); connective tissue and joint structures (hypermobility); skeletal/osseous tissue (delayed maturation, scoliosis, pectus deformity).

Subcellular level: Nucleus/nucleoplasm and chromatin (site of SRCAP complex activity); nucleosome (site of H2A.Z exchange). GO Cellular Component: GO:0000812 (Swr1 complex), GO:0000786 (nucleosome), GO:0005634 (nucleus).

Localization (UBERON): Brain (UBERON:0000955), cerebral cortex (UBERON:0000956), hippocampus/dentate gyrus (UBERON:0001885/UBERON:0001885), skeletal system generally (UBERON:0001434), vertebral column (UBERON:0001130 — scoliosis), thoracic wall/sternum (UBERON:0001491 — pectus deformity). Findings are generally bilateral/systemic rather than lateralized, consistent with a chromatin-remodeling disorder affecting global developmental programs.

8. Temporal Development

Onset: Congenital/early childhood onset — developmental delay and hypotonia are typically apparent in infancy/early childhood; the disorder is classified as an early-onset neurodevelopmental disorder.

Onset pattern: Insidious/developmental rather than acute; behavioral/psychiatric features (ADHD, anxiety, tics, psychosis) may emerge or become more apparent later in childhood or adolescence.

Progression: Neurodevelopmental impairment is generally static/stable rather than degenerative (consistent with a congenital chromatin-regulatory disorder), though individual comorbidities (musculoskeletal pain, scoliosis, psychiatric symptoms) may evolve or worsen with growth and age. No formal staging system exists given the disorder's rarity and recent delineation.

Disease course pattern: Chronic, lifelong; not episodic or relapsing-remitting in its core neurodevelopmental features, though seizures (in the minority who have them) and psychiatric symptoms may be episodic.

Recently expanded phenotypic spectrum: A 2026 Epilepsia study (Liang et al., PMID:41144712) reports that more severely damaging de novo SRCAP variants (truncating or missense variants predicted to cause significant hydrophobicity/stability disruption) are associated with a developmental and epileptic encephalopathy (DEE) phenotype in a subset of patients (n=5), while milder-damage, biallelic variants were found in a separate group with focal epilepsy (n=6, including refractory cases) — suggesting a genotype-severity-phenotype gradient across the SRCAP-related disease spectrum from focal epilepsy → DEHMBA → DEE, and that variant "damage" (structural/hydrophobicity impact) may correlate with epilepsy severity and outcome. This is a very recent, still-emerging finding that meaningfully broadens the SRCAP-related disease spectrum beyond the 2021 DEHMBA and classic FLHS entries and merits close attention for future curation/entry-scope decisions.

Critical periods: Not formally established; as with most neurodevelopmental chromatinopathies, early childhood is presumed to be the critical window for developmental/behavioral intervention, though no DEHMBA-specific intervention-timing studies exist.

9. Inheritance and Population

Epidemiology: DEHMBA is an ultra-rare, recently delineated disorder; no formal population prevalence or incidence estimate has been published. Fewer than ~50 individuals have been reported in the literature to date (33 in the founding Rots et al. 2021 cohort, plus subsequent case reports — the intronic-variant case, the SVA-insertion case, and the newly reported DEE/focal-epilepsy expansion cohort). Given its very recent recognition (2021) and ongoing case ascertainment (as recently as 2026), prevalence is almost certainly under-ascertained.

Inheritance pattern: Autosomal dominant, virtually always de novo. No inherited transmission has been reported in the founding cohort (consistent with a severe, LoF-intolerant gene under strong purifying selection against inherited transmission of pathogenic variants, though the 2026 Epilepsia paper's report of biallelic variants in a distinct focal-epilepsy subgroup suggests inheritance patterns may be more heterogeneous across the full SRCAP phenotypic spectrum than in DEHMBA alone).

Penetrance: Presumed complete/high given exclusively de novo occurrence and consistent phenotype across unrelated probands, though formal penetrance estimates are not available for such a rare disorder.

Expressivity: Markedly variable — this is one of the disorder's defining features, especially in the musculoskeletal/craniofacial domain (in contrast to the tightly stereotyped FLHS gestalt). Severity of intellectual disability, presence/absence of seizures, and psychiatric comorbidity all vary substantially across reported patients.

Genetic anticipation: Not applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for DEHMBA, though it is a theoretical consideration for recurrence risk counseling in any de novo dominant disorder.

Founder effects / consanguinity: No founder mutations reported; disorder is de novo and pan-ethnic in the cases reported to date.

Carrier frequency: Not applicable to a de novo dominant disorder without population carrier screening data.

Population demographics: No specific ethnic, geographic, or sex-ratio enrichment has been reported in the literature reviewed; the founding cohort was assembled through international collaboration (implying broad geographic representation across contributing centers, likely predominantly Europe/North America given the authorship and GeneMatcher-style ascertainment, though exact per-country breakdown was not retrieved in this search).

10. Diagnostics

Clinical/genetic testing: - First-tier: Exome sequencing (trio, proband + parents) to identify de novo heterozygous truncating/LoF SRCAP variants — the primary diagnostic approach used in the founding cohort. - Second-tier / when exome is non-diagnostic despite strong clinical suspicion: Combined exome + whole transcriptome (RNA) sequencing, which identified a deep intronic splice-altering variant missed by DNA-only exome analysis (Yamamoto et al. 2024) — an important diagnostic-methodology point for genetically unresolved suspected cases. - Structural variant detection: Standard short-read exome/genome pipelines may miss retrotransposon (e.g., SVA) insertions; specialized structural-variant-calling algorithms or long-read sequencing may be required, as illustrated by the 2022 exon-13 SVA insertion case. - Chromosomal microarray (CMA): relevant to exclude/detect a 16p11.2 deletion encompassing SRCAP, which can produce an overlapping phenotype. - DNA methylation episignature testing (EpiSign): A validated, clinically available adjunct diagnostic tool — DEHMBA (non-hotspot truncating SRCAP variants) has a distinct genome-wide methylation signature separable from FLHS and from unaffected controls, useful for resolving variants of uncertain significance in SRCAP and for supporting diagnosis in genetically undiagnosed individuals with a compatible phenotype.

Clinical criteria / differential diagnosis: No formal consensus diagnostic criteria (DSM/ICD-style) exist given the disorder's recent delineation; diagnosis rests on molecular confirmation of a qualifying de novo SRCAP variant in the appropriate clinical context. Key differential diagnoses include: - Floating-Harbor syndrome (same gene, different variant location; distinguished by short stature, brachydactyly, delayed bone age, and characteristic facial gestalt, which are absent or much milder in DEHMBA). - Classic 16p11.2 BP4–BP5 recurrent microdeletion/duplication syndrome (a different, larger CNV interval; distinguish from focal SRCAP-only deletions). - Other SATB2-related and chromatin-remodeling neurodevelopmental disorders (SATB2-associated syndrome, given the mechanistic Satb2 link) and other autism-associated chromatinopathies more broadly, given overlapping ID/ASD/hypotonia phenotypes. - The newly described SRCAP-related DEE / focal epilepsy phenotypic extremes (Liang et al. 2026) should be considered part of a broader SRCAP-related spectrum when epilepsy is a prominent early feature.

Screening: No population or newborn screening program exists (not applicable to this ultra-rare, individually ascertained disorder); diagnosis is case-by-case via clinical exome/genome sequencing.

11. Outcome / Prognosis

No formal survival, mortality, or long-term natural-history/longitudinal outcome data have been published for DEHMBA given its 2021 delineation and small reported cohort; there is no indication in the literature reviewed that DEHMBA is associated with reduced life expectancy or life-threatening organ involvement — the disorder's morbidity burden is dominated by neurodevelopmental (intellectual disability, speech delay), behavioral/psychiatric (autism, anxiety, aggression, tics, psychosis), and musculoskeletal (chronic pain, scoliosis) impacts on function and quality of life rather than by mortality risk. Prognostic factors (e.g., variant type/location, presence of seizures) have not been systematically studied; the emerging genotype-severity correlation reported in the 2026 Epilepsia SRCAP-DEE/focal-epilepsy expansion (variant "damage" correlating with epilepsy severity/outcome) may represent an early prognostic signal relevant to the broader SRCAP spectrum, but has not yet been validated specifically within DEHMBA.

12. Treatment

There is no disease-specific, mechanism-targeted therapy for DEHMBA; management is supportive/symptomatic, following general neurodevelopmental-disorder care models:

• Developmental/rehabilitative therapies: Physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351), and speech-language therapy (NCIT:C159273) for developmental delay, hypotonia, and speech impairment.
• Behavioral/psychiatric management: Behavioral therapy/counseling (NCIT:C181743) for autism spectrum features, ADHD, anxiety, and aggressive behavior; pharmacotherapy (NCIT:C15986) as clinically indicated for ADHD, anxiety, tics/Tourette syndrome, or psychosis (specific agents not systematically reported in the SRCAP-DEHMBA literature; management follows standard psychiatric practice for the specific comorbid symptom).
• Musculoskeletal/orthopedic care: Monitoring and, where indicated, orthopedic surgical procedure (NCIT:C16186) for scoliosis or symptomatic pectus deformity; supportive care for chronic musculoskeletal pain (NCIT:C15747).
• Seizure management: Standard antiseizure pharmacotherapy for the minority with epilepsy; the 2026 Epilepsia report's finding that focal-epilepsy-associated (biallelic, milder-damage) variants were "correlated with... outcomes" suggests genotype may eventually inform antiseizure treatment response expectations within the broader SRCAP spectrum, though this is not yet an actionable clinical guideline.
• Genetic counseling (NCIT:C15240): recommended given the de novo autosomal dominant inheritance pattern, with recurrence risk to future pregnancies generally low (baseline germline mosaicism risk) absent evidence of parental mosaicism.
• Experimental/preclinical: AAV-mediated Satb2 gene delivery ameliorated cellular and behavioral phenotypes in the Srcap+/- mouse model (Ding et al., 2023/2024) — a proof-of-concept, preclinical (mouse) finding suggesting a potential future targeted molecular strategy, but with no human clinical translation, trial, or NCT-registered study identified to date. This should be curated strictly as model-organism/computational-adjacent preclinical evidence, not as an available or emerging human treatment.

No clinical trials (ClinicalTrials.gov) specific to DEHMBA or SRCAP-related disorders were identified in this search.

13. Prevention

No primary, secondary, or tertiary prevention strategies exist for this de novo, non-preventable Mendelian disorder. Given its de novo, non-heritable-in-the-typical-sense pattern, prenatal/preimplantation genetic diagnosis is not routinely applicable except in the rare setting of documented parental germline mosaicism, and no such case has been reported. Genetic counseling remains the primary "preventive" intervention offered to families, focused on recurrence-risk discussion for future pregnancies (low, baseline de novo/mosaicism risk) rather than population-level prevention.

14. Other Species / Natural Disease

No naturally occurring veterinary/companion-animal disease attributable to spontaneous SRCAP variants has been reported (searched OMIA-type resources were not directly queried in this pass but no such reports surfaced in general literature search); DEHMBA-relevant animal data are limited to engineered mouse models (see Section 15). SRCAP is evolutionarily conserved (present with clear orthologs across vertebrates given its essential chromatin-remodeling function), consistent with the mouse ortholog Srcap (chromosome 7 F3 in mouse) being usable as a faithful genetic model.

15. Model Organisms

Mouse (Mus musculus): - Srcap+/- haploinsufficient mouse (Ding et al., 2023 bioRxiv preprint / 2024 published): the principal, best-characterized model. Recapitulates autism-relevant behavioral domains — impaired social novelty, repetitive/stereotyped behavior, anxiety-like behavior, and learning/memory deficits — plausibly modeling the ASD/behavioral-abnormalities component of the human DEHMBA phenotype, though it has not been evaluated for the musculoskeletal, craniofacial, or broader developmental-delay/intellectual-disability domains, and its fidelity to the full human DEHMBA phenotype (versus the narrower ASD component) is an open question — a candidate HUMAN_MODEL_MISMATCH consideration for curation. - Mechanistically, this model links Srcap haploinsufficiency → reduced H2A.Z occupancy at the Satb2 promoter → reduced Satb2 expression → parvalbumin+ interneuron loss (retrosplenial cortex, dentate gyrus) and dentate gyrus synaptic/dendritic abnormalities → behavioral phenotype, with AAV-Satb2 rescue of both cellular and behavioral phenotypes providing causal (interventional) support for this pathway. - Human iPSC-derived or organoid models: none identified in this search specific to SRCAP-DEHMBA. - Other species (zebrafish, Drosophila, C. elegans): no SRCAP/DEHMBA-specific disease models identified in this search, though SRCAP/SWR1-complex biology is studied more generally in yeast (Swr1, the SRCAP ortholog) and Drosophila (Domino) as basic chromatin-biology models rather than disease models per se.

Model limitations: The mouse model captures behavioral/ASD-relevant and interneuron/synaptic phenotypes but has not been reported to recapitulate the musculoskeletal (joint hypermobility, scoliosis, pectus deformity), craniofacial, or broader somatic growth features of human DEHMBA; translational fidelity for the full human syndrome (beyond the behavioral/ASD axis) remains unestablished.

Summary Table: Key Ontology Term Suggestions for KB Curation

Key Primary References

1. Rots D, Chater-Diehl E, Dingemans AJM, et al. "Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature." Am J Hum Genet. 2021;108(6):1053-1068. PMID: 33909990. — Founding paper delineating DEHMBA in 33 patients, establishing the episignature.
2. Yamamoto S, et al. "Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder." J Hum Genet. 2024. PMID: 38448605.
3. "A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene." 2022. PMID: 35768521.
4. Liang, et al. "De novo SRCAP variants cause developmental and epileptic encephalopathy and the phenotypic spectrum." Epilepsia. 2026;67:846-861. PMID: 41144712. — Expands the SRCAP-related phenotypic spectrum to DEE and focal epilepsy.
5. Ding C, Zhou W, Shi Y, et al. "Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression." bioRxiv 2023.07.03.547590 / published 2024. — Mouse model mechanistic study.
6. Hood RL, et al. "Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome." (foundational FLHS/SRCAP paper, ~2012).
7. OMIM #619595 (DEHMBA); OMIM *611421 (SRCAP); MedGen C5562012; MalaCards DVL013.

Notes for curation: Nearly all mechanistic (Satb2/H2A.Z/interneuron) data derive from a single mouse model and have not been directly confirmed in human tissue — flag as HUMAN_MODEL_MISMATCH if incorporated into a pathophysiology node. The 2026 Epilepsia paper substantially broadens the SRCAP-related phenotypic spectrum beyond DEHMBA/FLHS and may warrant a scope discussion (has_subtypes vs. related-entry) before curation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• HP:0034274 (1 mention) - the report calls it "Chronic pain"; HP calls it Gastrointestinal ulcer
• HP:0000768 (2 mentions) - the report calls it "Phenotype — pectus deformity"; HP calls it Pectus carinatum
• UBERON:0001130 (1 mention) - the report calls it "scoliosis"; UBERON calls it vertebral column
• UBERON:0001491 (1 mention) - the report calls it "pectus deformity"; UBERON calls it wrist joint
• NCIT:C15302 (1 mention) - the report calls it "Developmental/rehabilitative therapies: Physical therapy"; NCIT calls it Physical Therapy**

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0043486 (obsolete histone exchange) (2 mentions)
• GO:0031498 (obsolete chromatin disassembly) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0000750 (2 mentions) - the report calls it "Phenotype — speech delay"; HP calls it Delayed speech and language development, and lists "Speech delay" among its other names
• HP:0000717 (2 mentions) - the report calls it "Phenotype — autism"; HP calls it Autism
• HP:0000708 (1 mention) - the report calls it "Aggressive behavior"; HP calls it Atypical behavior
• HP:0000739 (2 mentions) - the report calls it "Phenotype — anxiety"; HP calls it Anxiety
• HP:0007018 (2 mentions) - the report calls it "Phenotype — ADHD"; HP calls it Attention deficit hyperactivity disorder, and lists "ADHD" among its other names
• HP:0000709 (2 mentions) - the report calls it "Phenotype — psychosis"; HP calls it Psychosis
• HP:0001252 (2 mentions) - the report calls it "Phenotype — hypotonia"; HP calls it Hypotonia, and lists "Central hypotonia" among its other names
• HP:0001250 (2 mentions) - the report calls it "Phenotype — seizures"; HP calls it Seizure, and lists "Epileptic seizure" among its other names
• HP:0001382 (2 mentions) - the report calls it "Phenotype — joint hypermobility"; HP calls it Joint hypermobility
• HP:0002650 (2 mentions) - the report calls it "Phenotype — scoliosis"; HP calls it Scoliosis
• NCIT:C181743 (1 mention) - the report calls it "Behavioral/psychiatric management: Behavioral therapy/counseling"; NCIT calls it Behavioral Counseling**, and lists "Behavioral Psychotherapy" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM.