ClinGen Dosage Sensitivity Curation Page

OPHN1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9582072 Billuart et al. (1998) report a female patient with intellectual disability and a balanced t(X;12) with a breakpoint within intron 2 of OPHN1. No normal gene products were detected by RT-PCR. They then reported a family with four males with intellectual disability across three generations who had a frameshift mutation. Carrier females were intellectually normal.
16221952 Zanni et al. (2005) report loss of function mutations in four families. In family A, a IVS2+2T>C splice site mutation was found in a 6-year old boy with hypotonia, strabismus, nystagmus, developmental delay, intellectual disability, and ataxic gait. This mutation led to skipping of exon 2 and a frameshift. No normal transcripts were detected. It was inherited from a normal mother. In family B, a deletion of exons 16 and 17 was found in six affected males whose features included intellectual disability, dysmorphic features, hypoplastic cerebellar vermis, and sometimes seizures. Carrier females were normal. In family C, four males with intellectual disability, dysmorphic features, and seizures were found to have a nonsense mutation. Their mother was not available for testing. In family D, three males with intellectual disability, dysmorphic features, and cerebellar anomalies were found to have a nonsense mutation, inherited from a normal mother.
20528889 Al-Owain et al. (2011) report a family with four boys and one girl with intellectual disability, seizures, cerebellar hypoplasia, and dysmorphic features who had a 68 kb deletion of exons 7-15. The girl had random X-inactivation. This deletion was inherited from a normal mother, but X-inactivation studies were not done for her. This paper also provides a review of all previous cases.

Haploinsufficiency phenotype comments:

In addition to the papers referenced above, additional reports of loss of function mutations resulting in intellectual disability, cerebellar anomalies, and consistent dysmorphic features can be found in PMID: 21796728, 18261018, 17304053, 12805098. See also patient 5 in Froyen et al (2007); PMID 17546640. In this family with affected males and OPHN1 deletion, the carrier mother was shown to have random X-inactivation. This suggests that X-inactivation status is not neccessarily predictive for penetrance in carrier females.

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

Triplosensitivity phenotype comment:

Focal duplications of OPHN1 alone have not been reported. Bedeschi et al.(2008, PMID: 18512229) report a male with intellectual disability, motor delays, seizures, scoliosis, asymmetry, and dysmorphic features that were different from those seen in patients with loss of function mutations in OPHN1. He had an 800 kb duplication of OPHN1 and two other genes that was inherited from his normal mother, who had skewed X-inactivation. Haplotype analysis showed that this likely originated from the maternal grandfather but he was not available for testing. A subsequent pregnancy was terminated at 21 weeks gestation due to hydrocephaly and cerebellar hypoplasia, but this duplication was not detected in that fetus.

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.