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Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (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 identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).; to: 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).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Tag watchlist tag was added to gene: PLEKHM1.
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Classified gene: PLEKHM1 as Amber List (moderate evidence)
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Added comment: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (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 identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Gene: plekhm1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.18 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159; 28290981
Skeletal dysplasia v2.17 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159
Skeletal dysplasia v2.16 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709
Skeletal dysplasia v2.9 PLEKHM1 Eleanor Williams commented on gene: PLEKHM1: 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.
Skeletal dysplasia v1.153 PLEKHM1 Eleanor Williams 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
Skeletal dysplasia v1.147 PLEKHM1 Tracy Lester reviewed gene: PLEKHM1: Rating: AMBER; Mode of pathogenicity: ; Publications: 27291868, 17997709, 17404618; Phenotypes: Osteopetrosis, autosomal recessive 6 - 611497, Osteopetrosis, autosomal dominant 3 - 618107; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v1.146 PLEKHM1 Eleanor Williams reviewed gene: PLEKHM1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v1.145 PLEKHM1 Eleanor Williams Source NHS GMS was added to PLEKHM1.