Heterozygous <i>WNT1</i> variant causing a variable bone phenotype

Alhamdi, Shatha; Lee, Yi-Chien; Chowdhury, Shimul; Byers, Peter H.; Taft, Ryan J.; Joeng, Kyu Sang; Lee, Brendan; Bird, Lynne M.

doi:10.1002/ajmg.a.40347

Cited by 13 publications

(14 citation statements)

References 15 publications

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“…Wnt1 promotes bone formation by binding to the LRP5-FZD receptor complex and activating the canonical WNT signalling pathway for promoting bone formation. Loss-of-function mutations in WNT1 result severe OI, severe skeletal abnormalities, white sclerae, or possible neurological defects [ 25 ]. Herein, we report four autosomal recessive (AR) forms of WNT1 variants and two are likely pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Mutational Screening of Skeletal Genes in 14 Chinese Children with Osteogenesis Imperfecta Using Targeted Sequencing

Tan

Qian

et al. 2022

Journal of Immunology Research

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Background. As a heterogeneous hereditary connective tissue disorder, osteogenesis imperfecta (OI) is clinically characterized by increased fracture susceptibility. Analysis of genetic pathogenic variants in patients with OI provides a basis for genetic counseling and prenatal diagnosis. Methods. In this study, 14 diagnosed OI patients from sporadic Chinese families were enrolled to be screened for potential mutations from these patients by next-generation sequencing technology. Results. 34 different variants were identified. 18 variants were from 4 OI-related genes including COL1A1, COL1A2, P3H1, and WNT1, and 10 variants are novel. Most OI patients (11 out of 14, 78%) harbor variants in type I collagen genes. Conclusions. Our results support previously established estimates of the distribution and prevalence of OI mutations and highlight both phenotype and genetic heterogeneity among and within families. We report several novel variants of OI, which expands the clinical spectrum of OI. In summary, our data provides disease-causing genes information for genetic counseling towards OI patients and families and also provides a reference for clinicians in the diagnosis of OI, also in prenatal diagnosis of this disease.

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Section: Discussionmentioning

confidence: 99%

Mutational Screening of Skeletal Genes in 14 Chinese Children with Osteogenesis Imperfecta Using Targeted Sequencing

Tan

Qian

et al. 2022

Journal of Immunology Research

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“…Other missense variants closest to residue 370 are Trp351Arg and Val355Phe, both located in the CTD of Wnt1 protein. The former has been reported in a family with early-onset osteoporosis ( 15 ) and the latter in a 35 year-old woman described with short stature, vertebral fractures, and early-onset osteoporosis. The same mutation was also detected in the heterozygous state in her mother who only presented osteoporosis after menopause ( 33 ).…”

Section: Discussionmentioning

confidence: 98%

“…WNT1 pathogenic variants described so far ( Figure 3 ) are associated with different pictures of bone fragility according to whether the variant was heterozygous or homozygous ( 13 – 17 , 30 – 46 ). In fact, patients carrying heterozygous variants exhibit normal growth, reduced bone mass or early-onset osteoporosis and fractures without appendicular deformities ( 13 – 15 , 42 ) ( Table 3 ), whereas those carrying homozygous variants display a life-threatening phenotype due to severe bone deformities ( 12 – 14 , 19 ). Notably, different Wnt proteins are expressed in bone, but Wnt1 is mainly responsible for bone homeostasis during skeletal development, bone mass accrual, and microarchitectural regulation ( 48 , 49 ).…”

Section: Discussionmentioning

confidence: 99%

“…The same mutation was also detected in the heterozygous state in her mother who only presented osteoporosis after menopause ( 33 ). Of note, in vitro studies observed that Trp351Arg had a significant reduced capacity to activate canonical Wnt signaling compared with the wild type ( 15 ). Conversely, Val355Phe is located in the ‘index finger’ of the Wnt1 protein.…”

Section: Discussionmentioning

confidence: 99%

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Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

et al. 2022

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The WNT1 gene is crucial for bone development and homeostasis. Homozygous mutations in WNT1 cause severe bone fragility known as osteogenesis imperfecta type XV. Moreover, heterozygous WNT1 mutations have been found in adults with early-onset osteoporosis. We identified a 35 year-old Caucasian woman who experienced multiple vertebral fractures two months after her second pregnancy. There was no history of risk factors for secondary osteoporosis or family history of osteoporosis. Dual-energy X-ray absorptiometry confirmed a marked reduction of bone mineral density (BMD) at the lumbar spine (0.734 g/cm2, Z-score -2.8), femoral neck (0.48 g/cm2, Z-score -3.5), and total hip (0.589 g/cm2, Z-score -3.0). Blood tests excluded secondary causes of bone fragility. Genetic analysis revealed a heterozygous missense mutation (p.Leu370Val) in the WNT1 gene. Varsome classified it as a variant of uncertain significance. However, the fact that the Leucine residue at position 370 is highly conserved among vertebrate species and the variant has a very low allelic frequency in the general population would exclude the possibility of a polymorphism. The patient was treated for two years with teriparatide therapy associated with calcium and vitamin D supplements. During the follow-up period she did not report further clinical fractures. After 24 months of teriparatide, BMD increased at lumbar spine (+14.6%), femoral neck (+8.3%) and total hip (+4.9%) compared to baseline. We confirm that the heterozygous WNT1 mutation could cause a variable bone fragility and low turnover osteoporosis. We suggest that teriparatide is one of the most appropriate available therapies for this case.

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“…Out of the five identified women, three had a history of at least one low-trauma non-vertebral fracture (wrist, humerus and/or hip fracture) accompanied by an osteopenic/osteoporotic BMD (average LS T-Score: −2.4, FN T-score: −2.8, TH T-score: −2.8), a 69-year old female had osteopenia at LS (T-score: −2.4) and hip (FN T-score: −1.1, TH T-score: −1.1), whereas the fifth individual, a 56-year old female, had a normal BMD at all anatomical sites (LS T-score: −0.3, FN T-score: 0.5, TH T-score: 1.5). The variable phenotypes seen in the relatives and unrelated women could possibly be explained by incomplete penetrance, development of the disease at a later stage, differing temporal and spatial activation of TGF- β 2 , or presence of risk factors, modifier genes and gene variants that might be altering the presenting phenotype [ 69 , 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

Cilia

Friggieri

Vassallo

et al. 2022

Genes

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Background: Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. Methods: Fifteen relatives aged between 28–74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication. Results: Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-β2 and ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-β2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype. Conclusions: Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections.

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Heterozygous WNT1 variant causing a variable bone phenotype

Cited by 13 publications

References 15 publications

Mutational Screening of Skeletal Genes in 14 Chinese Children with Osteogenesis Imperfecta Using Targeted Sequencing

Mutational Screening of Skeletal Genes in 14 Chinese Children with Osteogenesis Imperfecta Using Targeted Sequencing

Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

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