ClinGen Dosage Sensitivity Curation Page

MID1

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
23791568 Migliore et al 2013 (Eur J Med Genet): In 12 patients, the authors report missense, nonsense, small insertions and deletions in MID1 (Table 2; 3 de novo). Further, exonic deletions were also detected by MLPA. The affected individuals have the following MID1 variants: 2 missense variants, 2 maternally inherited nonsense variants, one de novo nonsense variant, one maternally inherited frameshift variant, one frameshift variant with unknown inheritance, one de novo deletion that extends upstream of MID1, two deletions with unknown inheritance, one deletion that is maternally inherited, and a maternally inherited duplication that leads to a frameshift and premature truncation.
29456483 Maia et al (2017 Mol Syndromology) reported two loss of function pathogenic frameshift MID1 variants. One of the variants was maternally inherited c.1656del and the other was de novo (c.1215_1228dup). This was observed in 2 unrelated families by sanger sequencing in a total of 4 males. Of note, authors mentioned that X-chromosome inactivation patterns in the blood of unaffected carrier females were not skewed. This is in concordance with previously published data by Pinson et al., 2004.
32656166 In a recent 2020 study (Front Pediatr), a frameshift loss of function pathogenic variant was identified p.(Lys444Glnfs*32) in MID1. This frameshift variant was found to occur de novo and the parents of the proband were healthy at the time of recruitment. As the family was lost to follow-up, clinical re-evaluation was not possible.
9354791 Quaderi et al. (Nat Gen, 1997) used Sanger sequence analysis to detect and describe some of the earliest variants in MID1 (predicted to be loss of function events). These variants include a 3-bp deletion involving a methionine codon, a 24-bp duplication causing the addition of 8 amino acids, and a 1-bp insertion resulting in a frameshift. The 3-bp deletion was found to segregate in the 5 affected members of the family but not in the 6 unaffected members and functional studies were not performed. Prior to this, evidence for an X-linked form of Optiz syndrome (OS) was provided by a large French family in which the disease appeared to co-segregate with a pericentric inversion of the X chromosome (inv(X)(p22.3q26)), possibly disrupting an important gene/locus. In one of the affected males with the inversion, Quaderi et al. investigated MID1 expression and RT-PCR analysis showed absence of MID1 expression in this affected male relative to a control locus.
11030761 Cox et al., (Human Mol Gen, 2000) identified thirteen males and two females exhibiting features consistent with X-linked Opitz syndrome. A de novo nonsense variant was identified (E115*) in MID1 in one participant. This variant is predicted to truncate the protein before the B-box motifs. An additional 2 nonsense variants of unknown inheritance were detected in this study, 1102C?T (R368*) in family OSP3 and 1483C?T (R495*) in family OSP9.
17221865

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.