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syndromic X-linked intellectual disability Najm type - Clinical Profile, Genes & Research | Kisho | Kisho

Features include always present findings: Hypoplasia of the pons, Microcephaly, Absent speech, and Feeding difficulties and others; and common findings: Short stature, Seizure, Low muscle tone (hypotonia), and Delayed ability to sit and others. 49 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	7	Moderate intellectual disability, Seizure, Absent speech
Eyes	5	Strabismus, Retinal coloboma, Nystagmus
Head and neck	4	Progressive microcephaly, Microcephaly, High palate
Muscles	3	Low muscle tone (hypotonia), Muscle weakness, Axial hypotonia
Ears	2	Hearing loss (hearing impairment), Inner ear hearing loss (sensorineural hearing impairment)
Growth and development	2	Short stature, Postnatal growth retardation
Digestive system	1	Feeding difficulties
Skin	1	Decreased sweating (hypohidrosis)
Bones and joints	1	Sideways curvature of the spine (scoliosis)

GeneReviews

Clinical Guidance

CASK disorders are more commonly reported in females and include a spectrum of phenotypes that differs in females and males:

Source: GeneReviews — "CASK Disorders"

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

CASK encodes calcium/calmodulin dependent serine protein kinase (926 aa). 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. Highest expression in Brain Cerebellar Hemisphere (12.2 TPM) and Artery Aorta (10.5 TPM).

Syndromic X-linked intellectual disability Najm type is associated with mutations in the CASK gene on chromosome X.

The CASK protein participates in LIN7, CASK and APBA1 bind, NRXNs bind CASK:Protein 4.1, and Interaction of IQGAP1 with nephrin pathways.

CASK is classified as a druggable target (Druggable Genome, Enzyme, Ion Channel, Kinase, Serine Threonine Kinase, and Transcription Factor categories) with score 0.0.

GeneReviews

Clinical Guidance

In females, microcephaly with pontine and cerebellar hypoplasia (MICPCH) is typically associated with heterozygous CASK pathogenic loss-of-function variants [, , , , ]. The X-linked intellectual disability (XLID) with or without nystagmus phenotype in females is typically associated with CASK hypomorphic pathogenic variants. In males, the three clinically distinguishable groups are associated with different classes of pathogenic CASK variants :

Source: GeneReviews — "CASK Disorders"

GeneReviews

Penetrance

Penetrance for the MICPCH phenotype (associated with the heterozygous CASK pathogenic loss-of-function variants) appears to be complete in the female individuals reported to date. Penetrance of CASK pathogenic variants appears to be complete in males. In males with mosaic CASK pathogenic variants the level of somatic mosaicism may be one factor that determines clinical variability. In females heterozygous for a pathogenic hypomorphic CASK variant penetrance is incomplete with high clinical variability.

Source: GeneReviews — "CASK Disorders"

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

CASK disorders are associated with a wide phenotypic spectrum ranging from mild-to-severe intellectual disability with or without nystagmus to moderate-to-profound intellectual disability and progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH), often associated with seizures. CASK disorders are X-linked and more commonly reported in females than in males. MICPCH in females is the most common phenotype to date.

Suggestive Findings

CASK disorders should be considered in individuals with intellectual disability of any degree and any of the following additional findings:

Source: GeneReviews — "CASK Disorders"

GeneReviews

Differential Diagnosis

Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH) Table 2. Genes of Interest in the Differential Diagnosis of MICPCH

Gene(s)	Disorder	MOI	Clinical Features	Brain MRI Findings
TSEN54	PCH2	AR	Generalized clonus ("jitteriness") w/lack of voluntary motor development later development of chorea spasticity, impaired swallowing, (in some) epilepsy; Persons w/PCH2 usually live into childhood.

Genetic testing for CASK is available. Testing is considered confirmatory for diagnosis.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for syndromic X-linked intellectual disability Najm type. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a CASK disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with CASK Disorders

System/Concern	Evaluation	Comment
Neurologic	Neurologic eval	To incl brain MRI EEG if not already done
Development	Developmental assessment	To incl motor, adaptive, cognitive, speech/language eval; Eval for early intervention / special education Psychiatric/
Behavioral	Neuropsychiatric eval	For individuals age 12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, /or traits suggestive of ASD
Musculoskeletal	Orthopedics / physical medicine rehab / PT OT eval	To incl assessment of:; Gross motor fine motor skills.; Scoliosis.; Mobility, activities of daily living, need for adaptive devices.; Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills). Gastrointestinal/
Feeding	Gastroenterology / nutrition / feeding team eval

Source: GeneReviews — "CASK Disorders"

GeneReviews

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "CASK Disorders"

Clinical Trials

View trials for syndromic X-linked intellectual disability Najm type

Explore Trials

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 5. Recommended Surveillance for Individuals with CASK Disorders

System/Concern	Evaluation	Frequency
Development	Monitor developmental progress educational needs.	At each visit Psychiatric/
Behavioral	Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior	—
Musculoskeletal	Physical medicine, OT/PT assessment of mobility, self-help skills	At each visit
Eyes	Ophthalmologic eval	Annually Hearing
Other	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) care coordination.	At each visit OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "CASK Disorders"

Phenotype severity distribution: 9 always present features, 12 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for syndromic X-linked intellectual disability Najm type.

96 publications have been identified in PubMed for syndromic X-linked intellectual disability Najm type. Kisho has analyzed 47 by research type. Research spans Case Report / Case Series (45%), Basic Science / Preclinical (26%), and Review / Meta-Analysis (17%).

Research Type	Count	% of Total
Patient case studies	21	45%
Laboratory research	12	26%
Research summaries	8	17%
Disease patterns and progression	6	13%

Recent Publications

Zhao Y (2026). [PMID: 41705901](https://pubmed.ncbi.nlm.nih.gov/41705901/). *Prenat Diagn*. [Review / Meta-Analysis]
Haanpää MK (2026). [PMID: 41236159](https://pubmed.ncbi.nlm.nih.gov/41236159/). *Am J Med Genet A*. [Case Report / Case Series]
Dutta D (2026). [PMID: 41741118](https://pubmed.ncbi.nlm.nih.gov/41741118/). *BMJ Case Rep*. [Case Report / Case Series]
Oktay MA (2026). [PMID: 42112678](https://pubmed.ncbi.nlm.nih.gov/42112678/). *J Pediatr Endocrinol Metab*. [Case Report / Case Series]
Mori T (2025). [PMID: 40422238](https://pubmed.ncbi.nlm.nih.gov/40422238/). *Cells*. [Basic Science / Preclinical]
Akaba Y (2025). [PMID: 40382977](https://pubmed.ncbi.nlm.nih.gov/40382977/). *Brain Dev*. [Review / Meta-Analysis]
Planté-Bordeneuve P (2025). [PMID: 39709004](https://pubmed.ncbi.nlm.nih.gov/39709004/). *Eur J Med Genet*. [Case Report / Case Series]
Braun D (2025). [PMID: 40265669](https://pubmed.ncbi.nlm.nih.gov/40265669/). *Am J Med Genet A*. [Case Report / Case Series]
Bottillo I (2025). [PMID: 40304357](https://pubmed.ncbi.nlm.nih.gov/40304357/). *Am J Med Genet A*. [Case Report / Case Series]
Fazio A (2025). [PMID: 41465117](https://pubmed.ncbi.nlm.nih.gov/41465117/). *Genes (Basel)*. [Review / Meta-Analysis]

Kisho

syndromic X-linked intellectual disability Najm type

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Penetrance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

syndromic X-linked intellectual disability Najm type

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Penetrance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team