syndromic X-linked intellectual disability Najm type

Summary

syndromic X-linked intellectual disability Najm type (MONDO:0010417) is a disease caused by CASK (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CASK (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 135
• Phenotypes (HPO): 46

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0001321	Cerebellar hypoplasia	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0012110	Hypoplasia of the pons	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000337	Broad forehead	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002553	Highly arched eyebrow	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011097	Epileptic spasm	Frequent (30-79%)
HP:0012171	Stereotypical hand wringing	Frequent (30-79%)
HP:0032794	Myoclonic seizure	Frequent (30-79%)
HP:0034353	Appendicular spasticity	Frequent (30-79%)
HP:0200134	Epileptic encephalopathy	Frequent (30-79%)
HP:0000609	Optic nerve hypoplasia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002317	Unsteady gait	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003508	Proportionate short stature	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0000543	Optic disc pallor	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Najm type
Mondo ID	MONDO:0010417
MeSH	C567466
OMIM	300749
Orphanet	163937
DOID	DOID:0060807
UMLS	C2677903
MedGen	437070
GARD	0012669
Is cancer (heuristic)	no

Also known as: intellectual disability and microcephaly with pontine and cerebellar hypoplasia · mental retardation and microcephaly with PONTINE and cerebellar hypoplasia · mental retardation and microcephaly with pontine and cerebellar hypoplasia · mental retardation, X-linked, syndromic, Najm type · MICPCH · MICPCH syndrome · microcephaly with pontine and cerebellar hypoplasia · syndromic X-linked intellectual disability Najm type · X-linked intellectual disability - microcephaly - pontocerebellar hypoplasia · X-linked intellectual disability-microcephaly-pontocerebellar hypoplasia syndrome

Data availability: 135 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › syndromic X-linked intellectual disability Najm type

Related subtypes (53): craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, Aase-Smith syndrome, arachnoid cyst, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dandy-Walker malformation-postaxial polydactyly syndrome, cervical hypertrichosis-peripheral neuropathy syndrome, Joubert syndrome with oculorenal defect, NPHP3-related Meckel-like syndrome, orofaciodigital syndrome type 6, X-linked intellectual disability-cerebellar hypoplasia syndrome, X-linked cerebral-cerebellar-coloboma syndrome syndrome, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, aprosencephaly cerebellar dysgenesis, Gomez-Lopez-Hernandez syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, pontine tegmental cap dysplasia, ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome, cerebellar-facial-dental syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal recessive spinocerebellar ataxia 20, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, isolated cerebellar vermis hypoplasia, cerebral gigantism-jaw cysts syndrome, holoprosencephaly-caudal dysgenesis syndrome, Joubert syndrome with ocular defect, macrocephaly-short stature-paraplegia syndrome, glioependymal/ependymal cyst, isolated cerebellar vermis agenesis, isolated unilateral hemispheric cerebellar hypoplasia, isolated bilateral hemispheric cerebellar hypoplasia, Hoyeraal-Hreidarsson syndrome, neural tube defect, partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, tubulinopathy-associated dysgyria, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, Ritscher-Schinzel syndrome, spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome, cystic malformation of the posterior fossa, pontocerebellar hypoplasia, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, hereditary cerebral malformation, isolated arhinencephaly

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

135 retrieved; paginated sample, class counts are floors:

58 pathogenic, 42 likely pathogenic, 16 uncertain significance, 9 pathogenic/likely pathogenic, 8 conflicting classifications of pathogenicity, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11530	NM_001367721.1(CASK):c.1915C>T (p.Arg639Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
11531	NM_001367721.1(CASK):c.915G>A (p.Lys305=)	CASK	Pathogenic	no assertion criteria provided
1343138	NM_001367721.1(CASK):c.2317+5G>A	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158066	NM_001367721.1(CASK):c.1644_1645del (p.Val549fs)	CASK	Pathogenic	criteria provided, single submitter
158069	NM_001367721.1(CASK):c.2041C>T (p.Arg681Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
158070	NM_001367721.1(CASK):c.2074C>T (p.Gln692Ter)	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158071	NM_001367721.1(CASK):c.20_27del (p.Leu7fs)	CASK	Pathogenic	criteria provided, single submitter
158074	NM_001367721.1(CASK):c.2485C>T (p.Gln829Ter)	CASK	Pathogenic	criteria provided, single submitter
158077	NM_001367721.1(CASK):c.430-2A>T	CASK	Pathogenic	criteria provided, single submitter
158082	NM_001367721.1(CASK):c.708+1G>A	CASK	Pathogenic	criteria provided, single submitter
158086	NM_001367721.1(CASK):c.82C>T (p.Arg28Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
158087	NM_001367721.1(CASK):c.880C>T (p.Gln294Ter)	CASK	Pathogenic	criteria provided, single submitter
1692990	NM_001367721.1(CASK):c.825G>A (p.Trp275Ter)	CASK	Pathogenic	criteria provided, single submitter
1784171	NM_001367721.1(CASK):c.1A>G (p.Met1Val)	CASK	Pathogenic	criteria provided, single submitter
180215	NM_001367721.1(CASK):c.1976G>A (p.Gly659Asp)	CASK	Pathogenic	criteria provided, single submitter
195200	NM_001367721.1(CASK):c.79C>T (p.Arg27Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
210581	NM_001367721.1(CASK):c.1981del (p.Leu661fs)	CASK	Pathogenic	criteria provided, single submitter
210585	NM_001367721.1(CASK):c.2392C>T (p.Gln798Ter)	CASK	Pathogenic	criteria provided, single submitter
210586	NM_001367721.1(CASK):c.2546_2547del (p.Glu849fs)	CASK	Pathogenic	criteria provided, single submitter
2138554	NM_001367721.1(CASK):c.2647C>T (p.Gln883Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
216899	NM_001367721.1(CASK):c.2318-2A>G	CASK	Pathogenic	criteria provided, single submitter
2431222	NM_001367721.1(CASK):c.2521-6A>G	CASK	Pathogenic	criteria provided, single submitter
2441639	NM_001367721.1(CASK):c.589G>T (p.Gly197Ter)	CASK	Pathogenic	criteria provided, single submitter
2446196	NM_001367721.1(CASK):c.1015+1G>A	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
2506011	NM_001367721.1(CASK):c.278+2_278+3del	CASK	Pathogenic	criteria provided, single submitter
2506584	NM_001367721.1(CASK):c.1811del (p.Leu604fs)	CASK	Pathogenic	criteria provided, single submitter
254208	NM_001367721.1(CASK):c.1465C>T (p.Arg489Trp)	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579274	GRCh38/hg38 Xp11.4(chrX:41333187-42099271)x1	CASK	Pathogenic	criteria provided, single submitter
2626912	NM_001367721.1(CASK):c.2080C>T (p.Gln694Ter)	CASK	Pathogenic	criteria provided, single submitter
265654	NM_001367721.1(CASK):c.2100G>A (p.Trp700Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
CASK	Definitive	X-linked	syndromic X-linked intellectual disability Najm type	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	gencc,clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cortical plate	1
hair follicle	1
adrenal tissue	1
lower lobe of lung	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASK	4,223
LDLR	1,426

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LDLR	P01130	36
CASK	O14936	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron clearance	1	1142.0×	0.016	LDLR
LDL clearance	1	271.9×	0.016	LDLR
Dopamine Neurotransmitter Release Cycle	1	248.3×	0.016	CASK
Nephrin family interactions	1	237.9×	0.016	CASK
Plasma lipoprotein clearance	1	237.9×	0.016	LDLR
Syndecan interactions	1	211.5×	0.016	CASK
Metabolism of fat-soluble vitamins	1	190.3×	0.016	LDLR
Visual phototransduction	1	129.8×	0.017	LDLR
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.017	CASK
Retinoid metabolism and transport	1	124.1×	0.017	LDLR
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.017	LDLR
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.017	CASK
Neurexins and neuroligins	1	98.5×	0.017	CASK
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.019	CASK
Metabolism of vitamins and cofactors	1	58.3×	0.025	LDLR
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.026	LDLR
Sensory Perception	1	47.6×	0.027	LDLR
Clathrin-mediated endocytosis	1	42.6×	0.029	LDLR
Membrane Trafficking	1	18.5×	0.062	LDLR
Vesicle-mediated transport	1	17.4×	0.062	LDLR
Transport of small molecules	1	12.6×	0.082	LDLR
Metabolism	1	5.8×	0.165	LDLR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of phosphatidylcholine catabolic process	1	4213.0×	0.003	LDLR
receptor-mediated endocytosis involved in cholesterol transport	1	4213.0×	0.003	LDLR
negative regulation of cellular response to growth factor stimulus	1	4213.0×	0.003	CASK
negative regulation of astrocyte activation	1	2808.7×	0.003	LDLR
plasma lipoprotein particle clearance	1	2106.5×	0.003	LDLR
negative regulation of receptor recycling	1	1685.2×	0.003	LDLR
positive regulation of lysosomal protein catabolic process	1	1685.2×	0.003	LDLR
cholesterol import	1	1404.3×	0.003	LDLR
high-density lipoprotein particle clearance	1	1203.7×	0.003	LDLR
lipoprotein catabolic process	1	1203.7×	0.003	LDLR
regulation of protein metabolic process	1	1053.2×	0.003	LDLR
negative regulation of protein metabolic process	1	1053.2×	0.003	LDLR
amyloid-beta clearance by cellular catabolic process	1	1053.2×	0.003	LDLR
negative regulation of microglial cell activation	1	1053.2×	0.003	LDLR
negative regulation of low-density lipoprotein particle clearance	1	766.0×	0.004	LDLR
response to caloric restriction	1	766.0×	0.004	LDLR
intestinal cholesterol absorption	1	702.2×	0.004	LDLR
positive regulation of triglyceride biosynthetic process	1	648.1×	0.004	LDLR
negative regulation of wound healing	1	648.1×	0.004	CASK
negative regulation of amyloid fibril formation	1	648.1×	0.004	LDLR
regulation of cholesterol metabolic process	1	561.7×	0.004	LDLR
low-density lipoprotein particle clearance	1	495.6×	0.004	LDLR
positive regulation of calcium ion import	1	468.1×	0.004	CASK
amyloid-beta clearance	1	468.1×	0.004	LDLR
negative regulation of cell-matrix adhesion	1	443.5×	0.004	CASK
cellular response to low-density lipoprotein particle stimulus	1	443.5×	0.004	LDLR
calcium ion import	1	401.2×	0.004	CASK
regulation of neurotransmitter secretion	1	383.0×	0.004	CASK
cholesterol transport	1	366.4×	0.004	LDLR
negative regulation of keratinocyte proliferation	1	351.1×	0.004	CASK

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CASK	FEDRATINIB
LDLR	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASK	9	4
LDLR	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
NILOTINIB	4	LDLR
LESTAURTINIB	3	CASK
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
BMS-387032	1	CASK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CASK	92	Binding:92
LDLR	55	Binding:54, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
NILOTINIB	4	LDLR
LESTAURTINIB	3	CASK
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
BMS-387032	1	CASK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CASK, LDLR
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.