intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type

Summary

intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type (MONDO:0026733) is a disease caused by NKAP (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NKAP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type
Mondo ID	MONDO:0026733
OMIM	301039
Orphanet	700325
UMLS	C5393302
MedGen	1716269
GARD	0025488
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type, X-linked recessive · MRXSHD

Data availability: 21 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 benign, 3 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685984	NM_024528.4(NKAP):c.961A>G (p.Met321Val)	NKAP	Pathogenic	criteria provided, single submitter
827656	NM_024528.4(NKAP):c.1010T>C (p.Ile337Thr)	NKAP	Pathogenic	no assertion criteria provided
827653	NM_024528.4(NKAP):c.998G>A (p.Arg333Gln)	NKAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827654	NM_024528.4(NKAP):c.988C>T (p.Arg330Cys)	NKAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827655	NM_024528.4(NKAP):c.989G>A (p.Arg330His)	NKAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1174111	NM_024528.4(NKAP):c.768G>T (p.Lys256Asn)	NKAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434366	NM_024528.4(NKAP):c.812A>T (p.Glu271Val)	NKAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434367	NM_024528.4(NKAP):c.128G>A (p.Arg43His)	NKAP	Uncertain significance	criteria provided, single submitter
2442002	NM_024528.4(NKAP):c.550A>G (p.Lys184Glu)	NKAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
2574140	NM_024528.4(NKAP):c.1073+1672_1074-1701del	NKAP	Uncertain significance	criteria provided, single submitter
2689586	NM_024528.4(NKAP):c.143C>G (p.Ser48Cys)	NKAP	Uncertain significance	criteria provided, single submitter
3220862	NM_024528.4(NKAP):c.1037C>T (p.Ser346Leu)	NKAP	Uncertain significance	criteria provided, single submitter
3241991	NM_024528.4(NKAP):c.250C>T (p.Pro84Ser)	NKAP	Uncertain significance	criteria provided, single submitter
3254832	NM_024528.4(NKAP):c.994C>T (p.Pro332Ser)	NKAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
4082019	NM_024528.4(NKAP):c.924-10_*10dup	NKAP	Uncertain significance	no assertion criteria provided
4532153	NM_024528.4(NKAP):c.1029A>C (p.Glu343Asp)	NKAP	Uncertain significance	criteria provided, single submitter
827657	NM_024528.4(NKAP):c.1082G>A (p.Arg361Gln)	NKAP	Uncertain significance	criteria provided, single submitter
1325903	NM_024528.4(NKAP):c.923+6C>T	NKAP	Benign	criteria provided, multiple submitters, no conflicts
1325904	NM_024528.4(NKAP):c.600ATC[1] (p.Ser202del)	NKAP	Benign	criteria provided, single submitter
1325905	NM_024528.4(NKAP):c.539-17A>T	NKAP	Benign	criteria provided, multiple submitters, no conflicts
1325906	NM_024528.4(NKAP):c.538+8T>A	NKAP	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NKAP	Strong	X-linked	intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKAP	Orphanet:700325	NKAP-related intellectual disability-facial dysmorphism-marfanoid habitus-scoliosis syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKAP	HGNC:29873	ENSG00000101882	Q8N5F7	NF-kappa-B-activating protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKAP	NF-kappa-B-activating protein	Acts as a transcriptional repressor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKAP	Other/Unknown	no		NKAP_C, NKAP

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKAP	245	ubiquitous	marker	calcaneal tendon, sural nerve, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKAP	1,791

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NKAP	Q8N5F7	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mRNA Splicing - Major Pathway	1	54.6×	0.018	NKAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.003	NKAP
granulocyte differentiation	1	1203.7×	0.003	NKAP
hematopoietic stem cell proliferation	1	648.1×	0.004	NKAP
T cell differentiation in thymus	1	411.0×	0.005	NKAP
somatic stem cell population maintenance	1	247.8×	0.006	NKAP
Notch signaling pathway	1	141.6×	0.009	NKAP
negative regulation of DNA-templated transcription	1	31.6×	0.036	NKAP
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	NKAP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NKAP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NKAP

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NKAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.