Skeletal dysplasia
Gene: PLEKHM1
Osteopetrosis and related disorders SD gp - one apparently recessive case and 2 dominant. Insufficient data; Review on behalf of Tracy LesterCreated: 6 Mar 2019, 11:44 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Osteopetrosis, autosomal recessive 6 - 611497; Osteopetrosis, autosomal dominant 3 - 618107
Publications
Provisionally associated with ?Osteopetrosis, autosomal recessive 6 #611497 and Osteopetrosis, autosomal dominant 3 #618107 in OMIM.
2 biallelic and 2 monoallelic cases reported. Limited family segregation data and generally targeted sequencing of only a few candidate genes. A mouse model supports the role for this protein in bone re-absorption.
BIALLELIC
PMID: 17404618 - Van Wesenbeeck et al 2007 - report that loss of function variants in the PLEKHM1 gene are responsible for the osteopetrotic phenotype of the incisors absent (ia) rat. They then screened the coding sequence of the PLEKHM1 gene in 43 patients diagnosed with various forms of osteopetrosis and identified a patient with a homozygous G→A transition at position +1 of the donor splice site of intron 3. She was diagnosed with an autosomal-recessive intermediate form of the disease. Her parents, carriers of the mutation, were related to each other and were clinically normal. The oldest brother was heterozygous for the mutation and was clinically and radiologically normal. The youngest brother was homozygous for the mutation but had not yet developed clinical symptoms.
PMID: 28290981 - Moore et al 2017 - report 19 year old white male with history of fractures, as did 2 of his brothers, presenting with clinical osteopetrosis. Genetic testing using the CTGT Osteopetrosis NextGen sequencing panel, consisting of 13 genes associated with osteopetrosis, revealed 2 heterozygous missense mutations in PLEKHM1 (exon 4 and exon 7). No segregation data.
MONOALLELIC
PMID: 27291868 - Bo et al 2016 - report a middle‐aged Chinese man who presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in BMD. A novel de novo heterozygous mutation ( c.3051_3052delCA) in the PLEKHM1 gene was identified, after initial screening of ClCN7 and TNFSF11 genes found no disease causing variants. The patient's unaffected parents and children were also screen and were not found to have the deletion.
PMID: 17997709 - Del Fattore et al 2008 - describe a new heterozygous missense mutation (R714C) in the PLEKHM1 gene in a female Italian patient with generalized osteopenia and localized osteosclerosis, with a diagnosis of osteopetrosis of the skull, However they state that it is NOT a case of osteopetrosis, because in the patient, urine CTX, a marker of in vivo bone resorption, was normal, and in vitro assays of osteoclast formation and resorptive function showed no abnormalities. She was screened for variants only in ClC‐7 and PLEKHM1. No other family members were available for analysis.
MOUSE MODEL
PMID: 27777970 - Fujiwara et al 2016 - Plekhm1-deficient mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Loss of Plekhm1 increased cancellous bone mass due to decreased bone resorption without obvious defects in other tissues and organs.Created: 28 Jul 2020, 10:05 p.m. | Last Modified: 28 Jul 2020, 10:05 p.m.
Panel Version: 2.9
This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: PLEKHM1; Initial rating suggestion: amberCreated: 6 Mar 2019, 11:36 a.m.
Comment on list classification: Published reports include three variants in two cases of biallelic osteopetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identified by RNA-seq analysis of Xanthogranulomatous epithelial tumour in a patient with osteopetrosis, however, the zygosity of this variant was not reported (PMID 32415263).Created: 17 Sep 2020, 1:43 p.m. | Last Modified: 21 Sep 2020, 10:52 a.m.
Panel Version: 2.19
Listed as associated with Skeletal Dysplasia by Gene Advisor (June 2016), Steve AbbsCreated: 27 Jul 2016, 9:50 a.m.
Comment when marking as ready: Not associated with phenotype in G2P. Two variants reported in this phenotype.Created: 8 Jul 2016, 10:20 a.m.
Comment on list classification: Tier 2 gene for skeletal dysplasia (Ana Beleza)Created: 8 Jul 2016, 10:15 a.m.
Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)Created: 21 Jun 2016, 1:02 p.m.
Tier 1Created: 17 Jun 2016, 8:07 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Osteopetrosis, autosomal recessive 6 611497
Variants in this GENE are reported as part of current diagnostic practice
Tag watchlist tag was added to gene: PLEKHM1.
Gene: plekhm1 has been classified as Amber List (Moderate Evidence).
Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159; 28290981
Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159
Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709
Added phenotypes Osteopetrosis, autosomal recessive 6 - 611497; Osteopetrosis, autosomal dominant 3 - 618107 for gene: PLEKHM1 Publications for gene PLEKHM1 were changed from 17997709 to 17404618; 27291868; 17997709
Source NHS GMS was added to PLEKHM1.
Promoted to version 1 9th August 2016
This gene has been classified as Red List (Low Evidence).
Mode of inheritance for PLEKHM1 was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for PLEKHM1 were set to 17997709
Phenotypes for PLEKHM1 were set to Osteopetrosis, autosomal recessive 6 611497
PLEKHM1 was added to Unexplained skeletal dysplasiapanel. Sources: Expert list,Radboud University Medical Center, Nijmegen,UKGTN
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Green List (High Evidence).
PLEKHM1 was added to Unexplained skeletal dysplasiapanel. Sources:
PLEKHM1 was created by sleigh