Human Gene Module / Chromosome X / TMLHE

TMLHEtrimethyllysine hydroxylase, epsilon

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 10
Rare Variants / Common Variants
13 / 1
Aliases
TMLHE, BBOX2,  FLJ10727,  TMLD,  TMLH,  XAP130
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
ID
Relevance to Autism

A rare mutation in the TMLHE gene has been identified with autism (Celestino-Soper et al., 2011). In a follow-up study, TMLHE deficiency caused by deletion of exon 2 was shown to be 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (Celestino-Soper et al., 2012). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

Molecular Function

This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine plays an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TMLHE (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE Celestino-Soper PB , et al. (2011) Yes -
2 Support A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism Celestino-Soper PB , et al. (2012) Yes -
3 Recent Recommendation Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE Nava C , et al. (2012) Yes ID
4 Support Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders Lim ET , et al. (2013) Yes -
5 Recent Recommendation Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation Ziats MN , et al. (2015) Yes Developmental regression
6 Support - Hu C et al. (2022) Yes -
7 Support - Miyake N et al. (2023) Yes -
8 Support - Hu C et al. (2023) Yes -
9 Support - Sheth F et al. (2023) Yes DD, ID
10 Negative Association - Liepinsh E et al. (2023) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.502C>T p.Gln168Ter stop_gained Unknown - - 35741772 Hu C et al. (2022)
c.640G>T p.Glu214Ter stop_gained Familial Maternal - 37007974 Hu C et al. (2023)
c.359-2A>G - splice_site_variant Unknown - Unknown 23352160 Lim ET , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 21865298 Celestino-Soper PB , et al. (2011)
c.229C>T p.Arg77Ter stop_gained Familial Maternal Multiplex 23092983 Nava C , et al. (2012)
c.730G>C p.Asp244His missense_variant Familial Maternal Simplex 23092983 Nava C , et al. (2012)
c.826T>A p.Tyr276Asn missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.1107G>T p.Glu369Asp missense_variant Familial Maternal Simplex 23092983 Nava C , et al. (2012)
c.443C>T p.Pro148Leu missense_variant Familial Maternal Simplex 36973392 Miyake N et al. (2023)
c.1045G>T p.Val349Phe missense_variant Unknown - Simplex 22566635 Celestino-Soper PB , et al. (2012)
c.209G>A p.Arg70His missense_variant Familial Maternal Simplex 22566635 Celestino-Soper PB , et al. (2012)
c.859G>A p.Glu287Lys missense_variant Familial Maternal Simplex 22566635 Celestino-Soper PB , et al. (2012)
c.961_962del p.Ile321LeufsTer5 frameshift_variant Familial Maternal Simplex 25943046 Ziats MN , et al. (2015)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 22566635 Celestino-Soper PB , et al. (2012)
SFARI Gene score
2

Strong Candidate

A rare mutation in the TMLHE gene has been identified with autism (PMID 21865298). TMLHE deficiency caused by deletion of exon 2 was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (PMID 22566635). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. More recently, a nonsense variant in TMLHE was identified in two brothers with autism and ID, but not in other healthy male family members (PMID 23092983); two missense variants in this gene were also identified in male ASD cases from simplex families in this report.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A rare mutation in the TMLHE gene has been identified with autism (PMID 21865298). TMLHE deficiency caused by deletion of exon 2 was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (PMID 22566635). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. More recently, a nonsense variant in TMLHE was identified in two brothers with autism and ID, but not in other healthy male family members (PMID 23092983); two missense variants in this gene were also identified in male ASD cases from simplex families in this report.

Reports Added
[New Scoring Scheme]
4/1/2015
3
icon
3

Decreased from 3 to 3

Description

A rare mutation in the TMLHE gene has been identified with autism (PMID 21865298). TMLHE deficiency caused by deletion of exon 2 was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (PMID 22566635). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. More recently, a nonsense variant in TMLHE was identified in two brothers with autism and ID, but not in other healthy male family members (PMID 23092983); two missense variants in this gene were also identified in male ASD cases from simplex families in this report.

Reports Added
[Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation.2015]
1/1/2015
3
icon
3

Decreased from 3 to 3

Description

A rare mutation in the TMLHE gene has been identified with autism (PMID 21865298). TMLHE deficiency caused by deletion of exon 2 was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (PMID 22566635). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. More recently, a nonsense variant in TMLHE was identified in two brothers with autism and ID, but not in other healthy male family members (PMID 23092983); two missense variants in this gene were also identified in male ASD cases from simplex families in this report.

Reports Added
[Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.2013]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

A rare mutation in the TMLHE gene has been identified with autism (PMID 21865298). TMLHE deficiency caused by deletion of exon 2 was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (PMID 22566635). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. More recently, a nonsense variant in TMLHE was identified in two brothers with autism and ID, but not in other healthy male family members (PMID 23092983); two missense variants in this gene were also identified in male ASD cases from simplex families in this report.

4/1/2014
No data
icon
3

Increased from No data to 3

Description

A rare mutation in the TMLHE gene has been identified with autism (PMID 21865298). TMLHE deficiency caused by deletion of exon 2 was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (PMID 22566635). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. More recently, a nonsense variant in TMLHE was identified in two brothers with autism and ID, but not in other healthy male family members (PMID 23092983); two missense variants in this gene were also identified in male ASD cases from simplex families in this report.

Krishnan Probability Score

Score 0.44600025874204

Ranking 15067/25841 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 0.0027629200535408

Ranking 11052/18225 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 0.92781558438416

Ranking 10762/18665 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
Larsen Cumulative Evidence Score

Score 21

Ranking 102/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.35569095084357

Ranking 17890/20870 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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