NEXMIF

Gene Facts

• HGNC Symbol: NEXMIF (HGNC:29433)
• HGNC Name: neurite extension and migration factor
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: KIAA2022
• Alias symbols: XPN, MRX98, KIDLIA
• %HI: 29.47
• pLI: 1
• LOEUF: 0.2
• Cytoband: Xq13.3
• Genomic Coordinates:

  GRCh37/hg19:	chrX:73952691-74145287
  GRCh38/hg38:	chrX:74732856-74925452

• MANE Select Transcript: NM_001008537.3 ENST00000055682.12
• Function: Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway. May act by regulating expression of protein-coding genes, such as N-cadherins and integrin beta-1 (ITGB1). {ECO:0000250|UniProtKB:D3ZGX1}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-35093
• ClinGen Curation ID: CCID:007546
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 06/26/2019

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• X-linked intellectual disability, Cantagrel type

HI Evidence

• PUBMED: 2756881
  Van Maldergem et al. (2013), studied 8 male patients (4 families) with X-linked intellectual disability and likely pathogenic mutations in the NEXMIF gene. The c.186delC and c.3597dupA NEXMIF truncating mutations were identified by X-chromosome exome sequencing, while array-CGH discovered a 70 kb microduplication encompassing NEXMIF exon 1 in the third family. All patients presented moderate-to-severe ID with autistic features and strabismus. Morphometric studies in cultured rat hippocampal neurons showed that siRNA-mediated NEXMIF knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for NEXMIF in neuron development and brain function.
• PUBMED: 27358180
  De Lange et al. (2016), reports 14 female carriers of a heterozygous de novo NEXMIF mutation. A wide mutation spectrum was reported, including 6 nonesense, 6 small dels, 1 gross del and 1 small insertion. All mutations were LoF, predicted to result in a frameshift or premature stop. The patients presented a neurodevelopmental disorder characterized by intellectual disability and epilepsy. X-inactivation was found to be random in 6 patients, while one patient showed complete skewing.
• PUBMED: 27568816
  Using whole-exome sequencing, Webster et al. (2016), studied 2323 females referred for developmental delay/ID. They identified a cohort of five unrelated females with de novo predicted pathogenic variants in NEXMIF. A wide mutation spectrum was reported, including 2 nonsense,1 frameshift, 1 small del and 1 small dup. All variants were confirmed by Sanger sequencing. The core phenotypic features included ID, developmental delay, impaired language and epilepsy refractory to Treatment.

• HI Evidence Comments: In males, pathogenic variants in NEXMIF cause a moderate to severe X-linked intellectual disability syndrome that is often associated with strabismus, hypotonia, microcephaly, postnatal growth retardation, motor delay, dysmorphic features, autistic behaviors and seizures (Van Maldergem et al., 2013). Females exhibit a broad phenotypic spectrum. Heterozygous female carriers of inherited variants have been reported to be unaffected (Van Maldergem et al., 2013; Charzewska et al., 2015), while females with de novo loss-of-function variants in NEXMIF present a phenotype with a less severe intellectual disability compared to hemizygous males, but is more often associated with severe and intractable myoclonic epilepsy (de Lange et al., 2016; Webster et al., 2017).

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Of note: Charzewska et al., 2015, studied a cohort of 134 Polish patients with X-linked intellectual disability. A duplication of Xq13.3 (chrX:73,899,064-74,262,928; hg19) was reported by array-CGH in 1 family with affected with X-linked intellectual disability. 5 affected males over two generations were identified, and obligatory female carriers were unaffected. The duplication contained the entire NEXMIF gene with large intergenic flanks of 118 kb and 54 kb pre-ceding and succeeding the gene. The variant co-segregated with ID phenotype in the family. By functional studies, the level of NEXMIF mRNA was measured in patient’s lymphocytes as well as fibroblasts, showing that the duplication reduced the NEXMIF expression level in patient’s lymphocytes by 66% and inhibited the expression in patient’s fibroblasts (96%). (PMID: 25394356)

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.