Human Gene Module / Chromosome 19 / NFIX

NFIXnuclear factor I/X (CCAAT-binding transcription factor)

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 23
Rare Variants / Common Variants
71 / 0
Aliases
NFIX, MRSHSS,  NF1A,  SOTOS2
Associated Syndromes
Sotos syndrome 2, Marshall-Smith syndrome
Chromosome Band
19p13.13
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report).

Molecular Function

The protein encoded by this gene is a transcription factor that binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3 in viral and cellular promoters.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NFIX (23 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome Malan V , et al. (2010) No ID, autistic traits, speech delay, outgrowth
2 Support Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature Klaassens M , et al. (2014) No DD, overgrowth, ASD
3 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No ID
4 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
5 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
6 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Macrocephaly
7 Recent Recommendation Further delineation of Malan syndrome Priolo M , et al. (2018) No Autistic features
8 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders Schluth-Bolard C , et al. (2019) No ID, macrocephaly
9 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
10 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No -
11 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
12 Support - Wang Q et al. (2022) No ADHD
13 Support - Levchenko O et al. (2022) No -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Spataro N et al. (2023) No -
16 Recent Recommendation - Timberlake AT et al. (2023) No -
17 Support - Wang J et al. (2023) Yes -
18 Support - Amerh S Alqahtani et al. (2023) No -
19 Support - M Cecilia Poli et al. () No -
20 Support - Tamam Khalaf et al. (2024) No -
21 Support - Marta Viggiano et al. (2024) Yes Malan syndrome, DD, ID, epilepsy/seizures
22 Support - Miriam E Reyna-Fabián et al. (2024) No ID
23 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (71)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 31178897 Gao C , et al. (2019)
- - copy_number_loss De novo - - 20673863 Malan V , et al. (2010)
- - copy_number_loss De novo - - 25118028 Klaassens M , et al. (2014)
- - translocation De novo - - 30923172 Schluth-Bolard C , et al. (2019)
- - copy_number_loss De novo - Simplex 35887114 Levchenko O et al. (2022)
c.568C>T p.Gln190Ter stop_gained De novo - - 20673863 Malan V , et al. (2010)
c.187G>T p.Glu63Ter stop_gained De novo - - 29897170 Priolo M , et al. (2018)
c.148A>T p.Lys50Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.28-13T>A - splice_site_variant De novo - - 29897170 Priolo M , et al. (2018)
c.328C>T p.Gln110Ter stop_gained De novo - - 29897170 Priolo M , et al. (2018)
c.463C>T p.Gln155Ter stop_gained De novo - - 29897170 Priolo M , et al. (2018)
c.520G>T p.Glu174Ter stop_gained De novo - - 29897170 Priolo M , et al. (2018)
c.694C>T p.Gln232Ter stop_gained De novo - - 29897170 Priolo M , et al. (2018)
c.759C>G p.Tyr253Ter stop_gained De novo - - 29897170 Priolo M , et al. (2018)
c.494C>G p.Ser165Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.559G>T p.Glu187Ter stop_gained De novo - - 28333917 Vissers LE , et al. (2017)
c.59T>C p.Leu20Pro missense_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.92T>C p.Phe31Ser missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.568C>T p.Gln190Ter stop_gained Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.112C>T p.Arg38Cys missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.113G>T p.Arg38Leu missense_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.182T>C p.Leu61Pro missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.248T>G p.Ile83Ser missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.280A>C p.Thr94Pro missense_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.1012C>T p.Gln338Ter stop_gained De novo - - 25118028 Klaassens M , et al. (2014)
c.317C>T p.Ser106Phe missense_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.325G>T p.Asp109Tyr missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.337A>G p.Lys113Glu missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.343C>T p.Arg115Trp missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.346C>G p.Arg116Gly missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.347G>A p.Arg116Gln missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.347G>A p.Arg116Gln missense_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.383G>A p.Arg128Gln missense_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.444G>C p.Glu148Asp missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.499C>A p.His167Asn missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.779C>G p.Thr260Ser missense_variant De novo - - 29897170 Priolo M , et al. (2018)
c.52G>A p.Asp18Asn splice_site_variant De novo - - 29897170 Priolo M , et al. (2018)
c.542dup p.Tyr181Ter frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.113G>A p.Arg38His missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.509G>A p.Cys170Tyr missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.370C>T p.Arg124Trp missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.371G>A p.Arg124Gln missense_variant Unknown - - 31036916 Lecoquierre F , et al. (2019)
c.97del p.Ala33LeufsTer32 frameshift_variant De novo - - 28708303 Chrot E , et al. (2017)
c.142del p.Met48CysfsTer9 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.294del p.Lys99SerfsTer36 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.859dup p.Glu287GlyfsTer5 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.361A>G p.Lys113Glu missense_variant De novo - Simplex 32277047 Chevarin M et al. (2020)
c.368G>A p.Arg115Gln missense_variant De novo - Simplex 32277047 Chevarin M et al. (2020)
c.157_177del p.Glu53_Glu59del inframe_deletion De novo - - 29897170 Priolo M , et al. (2018)
c.382del p.Leu128CysfsTer15 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.298del p.Val100CysfsTer2 frameshift_variant De novo - - 38177409 M Cecilia Poli et al. ()
c.935G>A p.Trp312Ter stop_gained Familial Maternal Multiplex 35266334 Wang Q et al. (2022)
c.1116del p.Ser373ProfsTer28 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.1117del p.Ser373ProfsTer28 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.43_49dup p.Glu17ValfsTer31 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.694C>T p.Gln232Ter stop_gained Familial Maternal Simplex 29897170 Priolo M , et al. (2018)
c.224T>C p.Leu75Pro missense_variant De novo - Simplex 38519481 Marta Viggiano et al. (2024)
c.200_201dup p.Lys68SerfsTer27 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.1496del p.Leu499ArgfsTer106 frameshift_variant De novo - - 27620904 Martnez F , et al. (2016)
c.(346C>T;348G>A] p.Arg116Ter stop_gained De novo - Simplex 32277047 Chevarin M et al. (2020)
c.154_155insT p.Glu52ValfsTer67 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.408delinsTT p.Leu136PhefsTer3 frameshift_variant Unknown - - 29897170 Priolo M , et al. (2018)
c.90_99del p.Trp30CysfsTer24 frameshift_variant De novo - - 25118028 Klaassens M , et al. (2014)
c.25_28dup p.Leu10GlnfsTer10 frameshift_variant De novo - Simplex 35266334 Wang Q et al. (2022)
c.1055_1064del p.Pro352LeufsTer46 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.322_323delinsA p.Pro108ThrfsTer27 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.412_413delinsG p.Lys138GlyfsTer73 frameshift_variant De novo - - 29897170 Priolo M , et al. (2018)
c.315_316insGGT p.Leu105_Ser106insGly inframe_insertion De novo - - 29897170 Priolo M , et al. (2018)
c.510C>A p.Val170%3D stop_gained Familial Paternal Simplex 37799141 Amerh S Alqahtani et al. (2023)
c.745_771delinsATGATGT p.Pro249MetfsTer36 frameshift_variant Unknown - Simplex 38909058 Miriam E Reyna-Fabián et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report). Clinical review of 45 novel individuals and 35 previously reported individuals with Malan syndrome in Priolo et al., 2018 determined that autistic features were present in 23 out of 74 individuals (31%) for whom such clinical data was available.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2020
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report). Clinical review of 45 novel individuals and 35 previously reported individuals with Malan syndrome in Priolo et al., 2018 determined that autistic features were present in 23 out of 74 individuals (31%) for whom such clinical data was available.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report). Clinical review of 45 novel individuals and 35 previously reported individuals with Malan syndrome in Priolo et al., 2018 determined that autistic features were present in 23 out of 74 individuals (31%) for whom such clinical data was available.

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report). Clinical review of 45 novel individuals and 35 previously reported individuals with Malan syndrome in Priolo et al., 2018 determined that autistic features were present in 23 out of 74 individuals (31%) for whom such clinical data was available.

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019]
4/1/2019
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report). Clinical review of 45 novel individuals and 35 previously reported individuals with Malan syndrome in Priolo et al., 2018 determined that autistic features were present in 23 out of 74 individuals (31%) for whom such clinical data was available.

Reports Added
[Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...2019]
7/1/2018
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report). Clinical review of 45 novel individuals and 35 previously reported individuals with Malan syndrome in Priolo et al., 2018 determined that autistic features were present in 23 out of 74 individuals (31%) for whom such clinical data was available.

Reports Added
[Further delineation of Malan syndrome.2018]
7/1/2017
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report).

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report).

Reports Added
[Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.2010] [Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature.2014] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017]
10/1/2016
S
icon
S

Score remained at S

Description

De novo monoallelic variants affecting the NFIX gene are responsible for two distinct syndromes: Sotos syndrome 2, also known as Malan syndrome, and Marshall-Smith syndrome (Malan et al., 2010). It was reported in Klaassens et al., 2014 that autistic traits have been reported in five cases with Malan syndrome (25%), including one case with a diagnosis of ASD (patient 1 in that report).

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
Krishnan Probability Score

Score 0.53619572191232

Ranking 1483/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.98906645519301

Ranking 1839/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.9357227862693

Ranking 12967/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.27820578000228

Ranking 3066/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Submit New Gene

Report an Error