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| Osteogenesis imperfecta v3.7 | WNT11 |
Achchuthan Shanmugasundram changed review comment from: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene. Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures. A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures. A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met). This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells. Sources: Literature; to: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene. Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures. A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures. A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met). This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells. This gene has not yet been reported with any phenotypes either in OMIM or in G2P. Sources: Literature |
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| Osteogenesis imperfecta v3.6 | WNT11 |
Achchuthan Shanmugasundram gene: WNT11 was added gene: WNT11 was added to Osteogenesis imperfecta. Sources: Literature Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WNT11 were set to 34875064 Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures Review for gene: WNT11 was set to GREEN Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene. Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures. A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures. A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met). This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells. Sources: Literature |
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| Osteogenesis imperfecta v2.13 | COMP | Arina Puzriakova Tag curated_removed tag was added to gene: COMP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v2.7 | KDELR2 |
Dmitrijs Rots gene: KDELR2 was added gene: KDELR2 was added to Osteogenesis imperfecta. Sources: Literature Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KDELR2 were set to PMID: 33053334 Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms Penetrance for gene: KDELR2 were set to Complete Review for gene: KDELR2 was set to GREEN Added comment: 4 families with osteogenesis imperfecta reported with functional studies reported in PMID: 33053334 Sources: Literature |
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| Osteogenesis imperfecta v2.6 | SGMS2 |
Zornitza Stark gene: SGMS2 was added gene: SGMS2 was added to Osteogenesis imperfecta. Sources: Expert list Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SGMS2 were set to 30779713; 32028018 Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550 Review for gene: SGMS2 was set to GREEN gene: SGMS2 was marked as current diagnostic Added comment: 12 patients from 6 unrelated families with the same stopgain variant (p.Arg50*), with osteoporosis that resembles osteogenesis imperfecta. In vitro over-expression assays of the variant demonstrate protein that was completely mislocalized in the cytosolic and nuclear compartments. 2 unrelated families were heterozygous for 2 missense (p.Ile62Ser, p.Met64Arg) with bone fragility and severe short stature, and spondylometaphyseal dysplasia. In vitro assays of each variant demonstrated an enhanced rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. Sources: Expert list |
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| Osteogenesis imperfecta v2.6 | MESD |
Eleanor Williams changed review comment from: Gene suggested by Alistair Pagnamenta. Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM. PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Sources: Literature; to: Gene suggested by Alistair Pagnamenta. Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM. PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Alistair Pagnamenta notes that there is a lack of sibling data. |
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| Osteogenesis imperfecta v2.4 | MESD |
Eleanor Williams gene: MESD was added gene: MESD was added to Osteogenesis imperfecta. Sources: Literature Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MESD were set to 31564437 Added comment: Gene suggested by Alistair Pagnamenta. Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM. PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Sources: Literature |
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| Osteogenesis imperfecta v2.3 | TAPT1 | Zornitza Stark reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365339; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v1.35 | B4GALT7 |
Eleanor Williams commented on gene: B4GALT7: Associated with Ehlers-Danlos syndrome, spondylodysplastic type, 1 (#130070) in OMIM. PMID: 26940150 - Salter et al 2016 - two unrelated patients with compound heterozygous mutations in B4GALT7. Both showed osteopenia (one with fractures, other patient had mild osteopenia). They review the phenotypes reported in previous cases (Table 1): 1 case with osteopenia reported in Faiyaz‐Ul‐Haque et al. [2004] , 1 case reported in Kresse et al. [1987] (with possible rib fracture). Summary: 3 cases of patients with homozygous or compound heterozygous variants in B4GALT7 and osteopenia, two with fractures. |
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| Osteogenesis imperfecta v1.19 | NBAS | Duncan Baker edited their review of gene: NBAS: Added comment: Following discussion with Dr Balasubramanian - rate green. Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI.; Changed publications: 27789416 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v1.19 | CREB3L1 | Duncan Baker edited their review of gene: CREB3L1: Added comment: Following discussion with Dr Balasubramanian - rate green. PMID: 29936144 Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta. A homozygous CREB3L1 stop codon mutation in a boy with severe OI, had blue sclera and tooth agenesis. Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%); however, collagen I levels were only reduced in hOBs (5-10%). Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to life-long bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures. PMID: 30657919 A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta. Identified the first homozygous pathogenic missense variant (p.(Ala304Val)) in a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain. In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability. In addition, overexpression of the mutant OASIS protein leads to decreased transcription of the SEC23A and SEC24D genes, which code for components of the coat protein complex type II (COPII), and aberrant OASIS signaling also results in decreased protein levels of SEC24D.; Changed publications: 29936144, 30657919; Changed phenotypes: Osteogenesis imperfecta, type XVI 616229 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v1.16 | NUDT6 |
Duncan Baker gene: NUDT6 was added gene: NUDT6 was added to Osteogenesis imperfecta. Sources: Expert list Mode of inheritance for gene: NUDT6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUDT6 were set to Essawi et al A homozygous missense variant in NUDT6 is responsible for an autosomal recessive form of osteogenesis imperfecta. Phenotypes for gene: NUDT6 were set to recurrent fractures, accompanied with other skeletal manifestations including short-limb dwarfism, mild frontal bossing, bowing of legs and scoliosis. Review for gene: NUDT6 was set to AMBER Added comment: New gene, one report linking to OI phenotype. Sources: Expert list |
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