ClinGen Dosage Sensitivity Curation Page

TMLHE

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21865298 Celestino-Soper et al., 2011 performed array CGH on 99 trios from the Simons Simplex Collection autism family collection and identified a maternally inherited intragenic TMLHE exon 2 deletion in a male proband. The same deletion was noted to be present in a healthy CEPH male.
22566635 Celestino-Soper et al., 2012 showed that exon 2 deletions result in a loss-of-function and examined the frequency of TMLHE mutations in autism and control populations. From abstract: "TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). 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 (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%)."
23092983 Nava et al. 2012 performed NGS of the chromosome X exome for 12 unrelated families with two males affected with autism spectrum disorder (ASD) and identified a maternally inherited TMLHE nonsense mutation in one family that was absent from 508 healthy male controls. Screening an additional 501 unrelated male patients with ASD for mutations in the TMLHE coding sequence identified two maternally inherited missense mutations predicted to result in a loss-of-function that were absent from 765 healthy male controls. A separate assessment of intragenic TMLHE copy number variant frequency identified exon 2 deletions in one of 896 healthy male controls vs. 3 of 691 male patients with ASD, however one of the three ASD probands had an affected brother who did not carry the exon 2 deletion.

Haploinsufficiency phenotype comments:

The current opinion regarding TMLHE deficiency is that it represents a weak risk factor for autism in males, with an estimated penetrance of 2-4% (Celestino-Soper et al., 2012), however additional replication studies are necessary. Due to the relative prevalence of TMLHE mutations in healthy males in control populations, the significance of TMLHE nullisomy is uncertain at this time. Female carriers are presumed to be unaffected.

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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

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.