Intellectual disability - microarray and sequencing
Gene: FRMPD4Comment on list classification: Updated rating from Amber to Green on advice of Genomics England clinical team: four families with a relevant phenotype meets the criteria for a Green rating.Created: 15 Aug 2019, 1:18 p.m. | Last Modified: 15 Aug 2019, 1:18 p.m.
Panel Version: 2.1008
Comment on mode of inheritance: MOI set to X-linked dominant on advice of Genomics England clinical team, in view of the single reported female heterozygote with a relevant phenotype.Created: 15 Aug 2019, 1:17 p.m. | Last Modified: 15 Aug 2019, 1:17 p.m.
Panel Version: 2.1007
Further paper identified to indicated FRMPD4 is relevant to ID. PMID: 29267967 provides details of four unrelated families, two families, family 1 and 4 had already been identified and reported in PMID:25644381.
Family 2, two brothers, had a micro deletion of exon 2, their mother was heterozygous for the same micro deletion.
Family 3, two half-siblings (p.Arg286Ter) Their unaffected mother was heterozygous for the same deletion, a hetrozygous sister was mildly disabled.
No further segregation information for the two families was reported.
Some functional work performed but only for the frameshift variant that was reported in family 1.
Requesting support from clinical team as limited information on the extended families and the female affected in family 3 is the only heterozygous carrier who displays ID features.Created: 25 Jul 2019, 10:23 a.m. | Last Modified: 25 Jul 2019, 1:04 p.m.
Panel Version: 2.977
Comment on publications: Added PMID: 29267967 from external review, to support this gene being upgraded to GreenCreated: 21 Feb 2019, 4:19 p.m.
Comment on mode of inheritance: reviewed MOI in view of external reviewCreated: 21 Feb 2019, 4:07 p.m.
Piard et al. (2018 - PMID: 29267967) provide clinical details on 10 males from 4 unrelated families (including the individuals reported by Hu et al. - PMID: 25644381) with FRMPD4 mutations.
ID was a feature in all individuals for whom this information was available (9/10 - from all 4 families). Seizures were observed in 3 individuals from 2 families.
- 1st family: 5 affected males harbored a frameshift variant (p.Cys618Valfs*8). 2 unaffected males were tested for segregation (details provided in the first report by Hu et al).
- 2nd family: Affected males from the second family were found to harbor a 66kb FRMPD4 intragenic deletion removing exon 2 (aa 16-54). Their unaffected mother was heterozygous for the same deletion.
- 3rd family: 2 males (half-sibs) harbored a nonsense variant inherited from their unaffected mother. A mildly affected sister was however found to be carrier of this variant. [All other carrier females in the 4 families described appeared to be unaffected].
- 4th family: A male subject was found to harbor a missense variant as a de novo event. This variant is presumed to affect protein function by a different mechanism than the others identified.
Segregation analyses in the 1st family included 2 unaffected males (details provided in the first report by Hu et al). Analyses for the other families are discussed in Fig.2 legend. The males in the 2nd and 3rd family did not have any unaffected sibs for eventual segregation studies. It is not specified whether studies were further extended in these families (the authors state that all variants segregated with the ID phenotype).
Functional studies were carried out only for the frameshift variant and demonstrated reduced interaction of FRMPD4 with Homer1 and PSD-95 (binding with Homer and PSD-95 is mediated by a Homer-binding motif and a C-terminal PDZ ligand, both downstream of the predicted premature termination codon). Binding with these proteins has been shown to be important for regulation of mGluR1/5 signaling in a previous study. Upon transfection of rat hippocampal neurons, the FRMPD4-WT construct increased spine density, which was not the case for the construct with the frameshift variant.
Frmpd4-KO mice exhibited deficit in hippocampus-dependent spatial learning and memory, as suggested by the Morris Water maze test.
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FRMPD4 is included in the DD panel of G2P, associated with intellectual disability (Disease confidence: probable).
In OMIM, this gene is associated with Mental retardation, X-linked 104, 300983. [OMIM notes that Carrier females may be mildly affected, reason why "X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)" was selected instead of the current MOI].
FRMPD4 is included in gene panels for ID offered by some diagnostic laboratories.
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As a result this gene could be possibly considered for upgrade to green (or remain amber pending further evidence).Created: 29 Jan 2019, 8:29 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Mental retardation, X-linked 104, 300983
Publications
Variants in this GENE are reported as part of current diagnostic practice
Candidate gene for ID in PMID 26350204 (Grozeva et al, 2015) and PMID: 24896178 (Gilissen et al, 2014). Probable DD gene for Intellectual Disability. A family with 5 affected males with a truncating variant, and an unrelated male with a de novo missense variant reported in PMID:25644381. Duplication of Xp22.2 including part of FRMPD4 in a family reported in PMID:20613765, also with duplication of Xq21.1 including HDX and deletion of Xq24 noncoding region.Created: 13 Dec 2017, 9:46 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Mental retardation, X-linked 104 300983
Publications
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Gene: frmpd4 has been classified as Green List (High Evidence).
Mode of inheritance for gene: FRMPD4 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: FRMPD4 were changed from Mental retardation, X-linked 104, 300983 to Mental retardation, X-linked 104, 300983; global developmental delay; intellectual disability
Publications for gene: FRMPD4 were set to 26350204; 24896178; 25644381; 20613765; 23871722
Phenotypes for gene: FRMPD4 were changed from Mental retardation, X-linked 104 300983 to Mental retardation, X-linked 104, 300983
Mode of inheritance for gene: FRMPD4 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Model of inheritance for gene FRMPD4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene FRMPD4 was set to ['26350204', '24896178', '25644381', '20613765', '23871722']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
FRMPD4 was added to Intellectual disabilitypanel. Source: Expert Review Red
FRMPD4 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory