NEXMIF

Chr XXLD

neurite extension and migration factor

Also known as: KIAA2022, KIDLIA, MRX98, XLID98, XPN

NCBI Gene: 340533ENSG00000050030UniProt: Q5QGS0

An inversion on the X chromosome which disrupts this gene and a G-protein coupled purinergic receptor gene located in the pseudoautosomal region of the X chromosome has been linked to X linked cognitive disability.[provided by RefSeq, Mar 2009]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 98MIM #300912
XLD
512
ClinVar variants
133
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— NEXMIF
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Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
133 Pathogenic / Likely Pathogenic· 255 VUS of 512 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.20LOEUF
pLI 1.000
Z-score 4.90
OE 0.06 (0.03–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.27Z-score
OE missense 0.85 (0.78–0.92)
464 obs / 547.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.03–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.78–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 2 / 31.9Missense obs/exp: 464 / 547.8Syn Z: -0.39

ClinVar Variant Classifications

512 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic121
Likely Pathogenic12
VUS255
Likely Benign102
Benign12
Conflicting10
121
Pathogenic
12
Likely Pathogenic
255
VUS
102
Likely Benign
12
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
44
0
77
0
121
Likely Pathogenic
8
0
4
0
12
VUS
0
247
8
0
255
Likely Benign
0
18
4
80
102
Benign
0
6
1
5
12
Conflicting
—10
Total522719485512

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NEXMIF · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NEXMIF-related intellectual disability and epilepsy (heterozygous)

strong
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

NEXMIF-related intellectual disability and epilepsy (hemizygous)

strong
Monoallelic X HemizygousUndeterminedUncertain
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked 98

MIM #300912

Molecular basis of disorder known

X-linked dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
X-Linked Epilepsies: A Narrative Review.
Bernardo P et al.·Int J Mol Sci
2024Review
NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.
Stamberger H et al.·Genet Med
2021
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.
Donnan AM et al.·Neurology
2023
Clinical spectrum of KIAA2022/NEXMIF pathogenic variants in males and females: Report of three patients from Indian kindred with a review of published patients.
Panda PK et al.·Brain Dev
2020Review
Gonadal mosaicism and paradoxical phenotype in NEXMIF encephalopathy: a case report of two siblings.
Adarsha N et al.·J Genet
2025Case report
NEXMIF pathogenic variants in individuals of Korean, Vietnamese, and Mexican descent.
Langley E et al.·Am J Med Genet A
2022
Infantile spasms caused by NEXMIF mutation: A case report and literature review.
Zhong L et al.·Appl Neuropsychol Child
2023Review
Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing.
Coppola A et al.·Epilepsia
2024
Novel NEXMIF gene pathogenic variant in a female patient with refractory epilepsy and intellectual disability.
Wu D et al.·Am J Med Genet A
2020Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Intellectual disorder type 98 caused by a novel NEXMIF variant: a case report and literature review.
Zhu Y et al.·Front Med (Lausanne)
2026🔓 Open AccessReview
A rare GCH1 p.Arg170Gly variant shows impaired enzymatic activity and co-occurs with a novel NEXMIF p.Asp155GlnfsTer2 leading to a complex neurological phenotype: functional studies and clinical aspects.
Ślusarczyk K et al.·Mol Genet Metab
2026Functional
Restoration of NEXMIF expression rescues abnormalities in gene transcription, neuron maturation and autistic-like behaviors in Nexmif knockout mice.
Odamah K et al.·Transl Psychiatry
2025🔓 Open Access
NEXMIF overexpression is associated with autism-like behaviors and alterations in dendritic arborization and spine formation in mice.
Odamah K et al.·Front Neurosci
2025🔓 Open Access
KIAA2022/NEXMIF c.1882C>T (p.Arg628*) Variant in a Romanian Patient with Neurodevelopmental Disorders and Epilepsy: A Case Report and Systematic Review.
Anastasescu CM et al.·Life (Basel)
2025🔓 Open AccessReview
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools