ClinGen Dosage Sensitivity Curation Page

FRMD7

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17013395 Tarpey et al. (2006): Mutations in FRMD7 were detected in 15 of 16 families with idiopathic congenital nystagmus (ICN) and linkage to this region. All mutations identified in FRMD7 co-segregated with disease in the linked families and were absent from 300 male control chromosomes. Detected mutations included two nonsense mutations (Q201X and R335X, which predict truncated proteins containing 28% and 47% of the protein respectively). Four of the five splice site mutations were at conserved splice donor residues (position +1 and +2) and are thus predicted to be pathological by classical exon skipping and nonsense mediated decay. Three frameshift variants were also reported. Though pedigrees for each family are provided in the supplemental material, the authors do not specify which individuals were tested. All families had multiple affected individuals; most families included affected females.
20450309 Fingert et al. (2010): Describes an intragenic deletion of exons 2-4 in a large, multi-generational family with ICN. Seven affected males, 2 affected females, 5 obligate carriers and 9 unaffected family members were assayed, with the variant segregating with disease in >8 family members. The deletion was not detected in unaffected males in the family or in 40 male control samples.
28378818 28378818 Thomas et al. (2017). DNA sequence and CNV analysis of 15 unrelated patients with Infantile nystagmus identified 3 probands with a pathogenic variant in FRMD7. A pathogenic frameshift variant c.1262delC: p.(Pro421LeufsTer23) was identified in family NYS-003, and found to segregate in 11 individuals. Affected individual NYS-007 was confirmed by MLPA analysis to have a heterozygous deletion of FRMD7 exons 2-12. 25678693 AlMoallem et al. (2015) analyzed the FRMD7 and GRP143 genes for 49 unrelated probands with X-linked idiopathic infantile nystagmus, using Sanger sequencing, NGS and MLPA-CNV analysis. They identified 9 unique FRMD7 variants predicted to be deleterious in 10 probands (2 female, 8 male). All variants were only found in affected individuals or obligate carriers. 24434814 Zhang et al. (2014) Performed PCR-based sequencing of FRMD7 and GPR147 in 4 unrelated families with X-linked idiopathic congenital nystagmus. The authors identified pathogenic FRMD7 variants in 3 of the families. Two of the identified variants; (p.Q487X and p.V549Y sX554) are predicted to generate nonfunctional truncated proteins, while the third variant, p.S260R, is predicted to disrupt the protein function. The variants co-segregated with affected individuals (12 males and 2 females) or obligate female carriers in the three families, and were not present in unaffected male family members or 200 normal controls

Haploinsufficiency phenotype comments:

Idiopathic congenital nystagmus (ICN) is usually inherited as an X-linked trait with incomplete penetrance in females. The phenotype is variable, even within families.

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.