Human Gene Module / Chromosome X / NEXMIF

NEXMIFneurite extension and migration factor

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 21
Rare Variants / Common Variants
37 / 0
Aliases
NEXMIF, KIAA2022,  KIDLIA,  MRX98,  XPN
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
Xq13.3
Associated Disorders
EPS, EP, ID, ASD, DD/NDD
Relevance to Autism

Maternally-inherited variants affecting the NEXMIF gene have been identified in male probands presenting with intellectual disability and autistic features (Cantagrel et al., 2004; Van Maldergem et al., 2013).

Molecular 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).

Reports related to NEXMIF (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males. Cantagrel V , et al. (2004) No -
2 Support Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Lim ET , et al. (2013) Yes -
3 Recent Recommendation Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth. Van Maldergem L , et al. (2013) No ASD
4 Recent Recommendation XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell-cell and cell-matrix adhesion and migration. Magome T , et al. (2013) No -
5 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support A duplication of the whole KIAA2022 gene validates the gene role in the pathogenesis of intellectual disability and autism. Charzewska A , et al. (2014) Yes -
7 Support Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features. Kuroda Y , et al. (2015) No Hypotonia, distinctive facial dysmorphisms
8 Support X-linked intellectual disability related genes disrupted by balanced X-autosome translocations. Moyss-Oliveira M , et al. (2015) Yes -
9 Support KIAA2022 nonsense mutation in a symptomatic female. Farach LS and Northrup H (2015) No Autistic behavior, microcephaly, short stature
10 Recent Recommendation De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. de Lange IM , et al. (2016) No ASD or autistic features
11 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
12 Support De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females. Webster R , et al. (2016) No -
13 Recent Recommendation The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and -Catenin Signaling. Gilbert J and Man HY (2016) No -
14 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
15 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
16 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Hamdan FF , et al. (2017) No DD/ID
17 Support Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature. Lorenzo M , et al. (2018) No Epilepsy/seizures
18 Support Novel NEXMIF pathogenic variant in a boy with severe autistic features, intellectual disability, and epilepsy, and his mildly affected mother. Lambert N , et al. (2018) No Autistic features
19 Support Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes. Moyss-Oliveira M , et al. (2019) No Microcephaly, short stature
20 Support NEXMIF/KIDLIA Knock-out Mouse Demonstrates Autism-Like Behaviors, Memory Deficits, and Impairments in Synapse Formation and Function. Gilbert J , et al. (2019) Yes -
21 Support Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures Tang S et al. (2020) No -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 27358180 de Lange IM , et al. (2016)
- - translocation De novo NA - 26290131 Moyss-Oliveira M , et al. (2015)
- - translocation De novo NA - 30700833 Moyss-Oliveira M , et al. (2019)
c.937C>T p.Arg313Ter stop_gained De novo NA - 27568816 Webster R , et al. (2016)
c.2707G>T p.Glu903Ter stop_gained De novo NA - 29693785 Lorenzo M , et al. (2018)
c.438C>A p.Cys146Ter stop_gained De novo NA - 27358180 de Lange IM , et al. (2016)
c.652C>T p.Arg218Ter stop_gained De novo NA - 27358180 de Lange IM , et al. (2016)
c.952C>T p.Gln318Ter stop_gained De novo NA - 27358180 de Lange IM , et al. (2016)
c.964C>T p.Arg322Ter stop_gained De novo NA - 27358180 de Lange IM , et al. (2016)
c.1441C>T p.Arg481Ter stop_gained De novo NA - 27358180 de Lange IM , et al. (2016)
c.1882C>T p.Arg628Ter stop_gained De novo NA - 27358180 de Lange IM , et al. (2016)
c.2707G>T p.Glu903Ter stop_gained De novo NA - 27479843 Lelieveld SH et al. (2016)
c.4411C>T p.Gln1471Ter stop_gained Unknown - Unknown 23352160 Lim ET , et al. (2013)
c.964C>T p.Arg322Ter stop_gained De novo NA Simplex 25900396 Kuroda Y , et al. (2015)
- - inversion Familial Maternal Multi-generational 15466006 Cantagrel V , et al. (2004)
- - copy_number_gain Familial Maternal Simplex 23615299 Van Maldergem L , et al. (2013)
c.2113C>T p.Gln705Ter stop_gained De novo NA Simplex 25900396 Kuroda Y , et al. (2015)
c.652C>T p.Arg218Ter stop_gained Unknown - Multiplex 29693785 Lorenzo M , et al. (2018)
c.2042del p.Gly681fs frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.4185del p.Lys1396fs frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.964C>T p.Arg322Ter stop_gained De novo NA Simplex 26576034 Farach LS and Northrup H (2015)
c.1262_1271del p.Leu421GlnfsTer76 frameshift_variant Unknown - - 32469098 Tang S et al. (2020)
c.422delA p.Gln141ArgfsTer7 frameshift_variant De novo NA - 27568816 Webster R , et al. (2016)
c.625dupC p.Leu209ProfsTer3 frameshift_variant De novo NA - 27568816 Webster R , et al. (2016)
c.3402C>A p.His1134Gln missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
- - copy_number_gain Familial Maternal Multi-generational 25394356 Charzewska A , et al. (2014)
c.2725del p.Ala909ProfsTer13 frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.1582delA p.Arg528GlufsTer4 frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.2999_3000delCT p.Ser1000Cysfs frameshift_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.3596_3597insA p.Lys1199Asnfs frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.2201_2202delAA p.Lys734SerfsTer24 frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.3053_3066del14 p.Gly1018AspfsTer2 frameshift_variant De novo NA - 27358180 de Lange IM , et al. (2016)
c.2774_2775insGAAA p.Asn926LysfsTer3 frameshift_variant Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.3470C>A p.Ser1157Ter stop_gained Familial Maternal Multi-generational 29717186 Lambert N , et al. (2018)
c.2937_2938insGAAAG p.Gln980GlufsTer32 frameshift_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.186del p.Gly63ValfsTer21 frameshift_variant Familial Maternal Multi-generational 23615299 Van Maldergem L , et al. (2013)
c.3597dupA p.Ser1200TyrfsTer5 frameshift_variant Familial Maternal Multi-generational 23615299 Van Maldergem L , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Maternally-inherited variants affecting the NEXMIF gene (formerly known as the KIAA2022 gene) have been identified in male probands presenting with intellectual disability and autism/autistic features (Cantagrel et al., 2004; Van Maldergem et al., 2013; Charzewska et al., 2015). De novo gene-disruptive variants in NEXMIF have also been identified in both male and female patients presenting with intellectual disability and ASD/autistic features (Kuroda et al., 2015; Moyses-Oliveira et al., 2015; Farach and Northrup et al., 2016). de Lange et al., 2016 identified 14 females with heterozygous de novo predicted loss-of-function variants that presented with intellectual disability and/or epilepsy; 6 of these cases also presented with autistic behavior, with one case being subsequently diagnosed with ASD (patient 1, as reported in the supplementary material). NEXMIF was shown to regulate neurite outgrowth in layer II/III mouse cortical neurons and cultured rat neurons via N-cadherin and -catenin signaling in Gilbert and Man, 2016. Male NEXMIF KO mice were found to demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory in Gilbert et al., 2019.

Score Delta: Score remained at 3

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2020
3
icon
3

Score remained at 3

Description

Maternally-inherited variants affecting the NEXMIF gene (formerly known as the KIAA2022 gene) have been identified in male probands presenting with intellectual disability and autism/autistic features (Cantagrel et al., 2004; Van Maldergem et al., 2013; Charzewska et al., 2015). De novo gene-disruptive variants in NEXMIF have also been identified in both male and female patients presenting with intellectual disability and ASD/autistic features (Kuroda et al., 2015; Moyses-Oliveira et al., 2015; Farach and Northrup et al., 2016). de Lange et al., 2016 identified 14 females with heterozygous de novo predicted loss-of-function variants that presented with intellectual disability and/or epilepsy; 6 of these cases also presented with autistic behavior, with one case being subsequently diagnosed with ASD (patient 1, as reported in the supplementary material). NEXMIF was shown to regulate neurite outgrowth in layer II/III mouse cortical neurons and cultured rat neurons via N-cadherin and -catenin signaling in Gilbert and Man, 2016. Male NEXMIF KO mice were found to demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory in Gilbert et al., 2019.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Maternally-inherited variants affecting the NEXMIF gene (formerly known as the KIAA2022 gene) have been identified in male probands presenting with intellectual disability and autism/autistic features (Cantagrel et al., 2004; Van Maldergem et al., 2013; Charzewska et al., 2015). De novo gene-disruptive variants in NEXMIF have also been identified in both male and female patients presenting with intellectual disability and ASD/autistic features (Kuroda et al., 2015; Moyses-Oliveira et al., 2015; Farach and Northrup et al., 2016). de Lange et al., 2016 identified 14 females with heterozygous de novo predicted loss-of-function variants that presented with intellectual disability and/or epilepsy; 6 of these cases also presented with autistic behavior, with one case being subsequently diagnosed with ASD (patient 1, as reported in the supplementary material). NEXMIF was shown to regulate neurite outgrowth in layer II/III mouse cortical neurons and cultured rat neurons via N-cadherin and -catenin signaling in Gilbert and Man, 2016. Male NEXMIF KO mice were found to demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory in Gilbert et al., 2019.

4/1/2018
icon
3.3

Increased from to 3.3

Description

3

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