Human Gene Module / Chromosome 22 / LZTR1

LZTR1Leucine-zipper-like transcription regulator 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
11 / 20
Rare Variants / Common Variants
32 / 0
Aliases
LZTR1, BTBD29,  LZTR-1,  SWNTS2
Associated Syndromes
Noonan syndrome 10, Noonan syndrome 2, Noonan syndrome 2, Noonan syndrome 10
Chromosome Band
22q11.21
Associated Disorders
ID
Relevance to Autism

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Molecular Function

Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the protein encoded by the LZTR1 gene subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. Mutations in the LZTR1 gene are responsible for autosomal-dominant and autosomal-recessive forms of Noonan syndrome (Yamamoto et al., 2015; Johnston et al., 2018; Pagnamenta et al., 2019).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LZTR1 (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome Yamamoto GL , et al. (2015) No -
3 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
5 Support Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants Johnston JJ , et al. (2018) No -
6 Recent Recommendation An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders Chen S , et al. (2018) No -
7 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
8 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes ID
9 Support Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome Pagnamenta AT , et al. (2019) No -
10 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
11 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
12 Support - Hiraide T et al. (2021) No -
13 Support - Mahjani B et al. (2021) Yes -
14 Support - Sheth H et al. (Nov-) No -
15 Support - Krgovic D et al. (2022) No Autistic behavior
16 Support - Zhou X et al. (2022) Yes -
17 Support - Hu C et al. (2023) Yes -
18 Support - Cirnigliaro M et al. (2023) Yes -
19 Support - Shenglan Li et al. (2024) No -
20 Support - Axel Schmidt et al. (2024) No ID
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.365C>A p.Ser122Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
- - copy_number_gain Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.433A>G p.Asn145Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.850C>T p.Arg284Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.993+1G>A - splice_site_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1549G>T p.Glu517Ter stop_gained De novo - - 31452935 Feliciano P et al. (2019)
c.1785+1G>C - splice_site_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.451G>A p.Asp151Asn missense_variant De novo - - 35813072 Krgovic D et al. (2022)
c.1943-256C>T - intron_variant Familial Maternal - 38593811 Shenglan Li et al. (2024)
c.509G>A p.Arg170Gln missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.1234C>T p.Arg412Cys missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2044A>G p.Lys682Glu missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1672C>T p.Gln558Ter stop_gained Familial Maternal - 35813072 Krgovic D et al. (2022)
c.603C>T p.Asp201%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1904C>T p.Pro635Leu missense_variant De novo - Simplex 34979677 Sheth H et al. (Nov-)
c.850C>T p.Arg284Cys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2178C>A p.Tyr726Ter stop_gained Familial Paternal - 38593811 Shenglan Li et al. (2024)
c.2062C>T p.Arg688Cys missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.180C>A p.Cys60Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.263+1G>A - splice_site_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1988G>T p.Gly663Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1018C>T p.Arg340Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.548A>T p.Tyr183Phe missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.1615+2T>C - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2306C>T p.Thr769Met missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2471T>C p.Leu824Pro missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.774del p.Phe258LeufsTer93 frameshift_variant Familial Maternal Simplex 30504930 Guo H , et al. (2018)
c.393dup p.Val132CysfsTer14 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2106del p.Asp703MetfsTer4 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2267dup p.Gln757AlafsTer25 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2487dup p.Asp830ArgfsTer21 frameshift_variant Familial Maternal Simplex 37506195 Cirnigliaro M et al. (2023)
c.1394_1395insT p.Arg466AlafsTer203 frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
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.

1/1/2021
1
icon
1

Score remained at 1

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.2015] [Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.2018] [Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
3
icon
3

Decreased from 3 to 3

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
3
icon
3

Decreased from 3 to 3

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.2018]
1/1/2016
icon
3

Increased from to 3

Description

An analysis of 2,377 families from the Simons Simplex Collection revealed statistically significant over-transmission of private likely gene-disruptive variants in the LZTR1 gene to ASD probands (6 inherited CNVs/SNVs in probands compared to none in unaffected siblings; inherited p-value=0.03) (Krumm et al., 2015).

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]
Krishnan Probability Score

Score 0.44061204531681

Ranking 19399/25841 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 3.3832300553859E-52

Ranking 18219/18225 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 0.94630857762908

Ranking 16818/18665 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 0.19943485826949

Ranking 4277/20870 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
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