<i>De novo</i> and inherited pathogenic variants in collagen‐related osteogenesis imperfecta

Zhytnik, Lidiia; Maasalu, Katre; Duy, Binh Ho; Pashenko, Andrey; Khmyzov, Sergey; Reimann, Ene; Prans, Ele; Kõks, Sulev; Märtson, Aare

doi:10.1002/mgg3.559

Cited by 14 publications

(11 citation statements)

References 29 publications

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“…Previous studies had illustrated the proportion of de novo mutations in OI with COL1A1 / COL1A2 mutations: 41.03% in South Korea ( 13 ), 56.16% in Estonia, Ukraine, and Vietnam ( 14 ), and 54.6% in our previous report ( 15 ). The percentage of de novo mutations in our study (37.78%) was significantly lower than our last report ( P = 0.0029), which may be due to we excluded cases without performing parental gene verification.…”

Section: Discussionsupporting

confidence: 48%

“…De novo mutations are genetically different from inherited mutations and are more damaging because mutation processes in de novo mutations are happening between generations without undergoing purifying selection (41). Zhytnik et al (14) revealed that in collagen-related OI, missense mutations and type III occupied a larger proportion in de novo mutations, and type I was lower compared with inherited mutations. In our study, the missense mutations in the de novo COL1A1 mutation group covered a higher proportion than in the inherited COL1A1 mutation group, though lacking significance, which may be a reason why there were more type III cases and higher clinical scores in the de novo mutation group.…”

Section: Discussionmentioning

confidence: 99%

“…Rare sporadic diseases in the population are associated with de novo mutations (12). In OI, nearly half of the cases are derived from de novo mutations (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have elucidated the genotype-phenotype correlation and mutation spectrum of collagen-related OI through large cohorts (15)(16)(17)(18), which contributes to achieving a more accurate and economical diagnosis of OI. However, in addition to some reports of de novo mutation cases in OI (16,19), few large cohort studies have compared de novo with inherited mutations in collagen-related OI (14). In this study, we enrolled 135 Chinese probands of OI with de novo or inherited COL1A1/ COL1A2 mutations in the department of Osteoporosis and Bone Disease of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, and then compared the gene mutation spectrum and phenotypic characteristics to investigate differences between de novo and inherited mutations among OI with COL1A1/COL1A2 mutations.…”

Section: Introductionmentioning

confidence: 99%

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Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta

Mei

Zhang

2022

Front. Endocrinol.

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PurposeNearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of COL1A1 and COL1A2 genes, of which de novo mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of de novo and inherited COL1A1/COL1A2 mutations of OI, assess the average paternal and maternal age at conception in de novo mutations, and research the rate of nonpenetrance in inherited mutations.Materials and MethodsA retrospective comparison between de novo and inherited mutations was performed among 135 OI probands with COL1A1/COL1A2 mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively.ResultsA total of 51 probands (37.78%) with de novo mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (P<0.001) and clinical scores (P<0.001) were significantly higher in de novo mutations. Missense mutations covered a slightly higher proportion of de novo COL1A1 mutations (46.34%) compared with inherited COL1A1 mutations (33.33%), however, lacking a significant difference (P=0.1923). The mean BMD Z/T-score at the lumbar spine in de novo mutations was -2.3 ± 1.5, lower than inherited mutations (-1.7 ± 1.8), but lacking statistical significance (P=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In de novo mutations, the average paternal and maternal age at conception was 29.2 (P<0.05) and 26.8 (P<0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50/51) with de novo mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20/78).ConclusionsOur data revealed that the proportion of clinical type III and clinical scores were significantly higher in de novo mutations than in inherited mutations, demonstrating that de novo mutations are more damaging because they have not undergone purifying selection.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

“…Rare sporadic diseases in the population are associated with de novo mutations (12). In OI, nearly half of the cases are derived from de novo mutations (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta

Mei

Zhang

2022

Front. Endocrinol.

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“…No cases of autosomal dominant inheritance were identified, which contradicts the literature. Based on previous studies of OI heritability in general, the frequency of de novo mutations was 41.03% in South Korea [ 16 ], 56.16% in Estonia, Ukraine and Vietnam [ 17 ], and in a study of 135 patients from China it was 37.78%. In the most recent study, the non-penetrance rate of hereditary proband parents was as high as 25.64%.…”

Section: Resultsmentioning

confidence: 99%

Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review

Tyurin

Merkuryeva

Zaripova³

et al. 2022

Biomedicines

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Osteogenesis imperfecta (OI) is a large group of genetically heterogeneous diseases resulting from decreased bone density and an abnormal microarchitecture, which are clinically manifested by abnormal bone fractures. A distinctive clinical feature of this group of diseases is the presence of spontaneous fractures and skeletal deformities. However, the clinical manifestations of different types of OI are characterized by marked polymorphism with variable severity of skeletal and extra-skeletal features. Previous studies have shown that a mutation (c.-14C>T) in the IFITM5 gene is responsible for autosomal dominant OI type V. However, the mutation has a variable expression pattern and marked clinical heterogeneity. In this study, a clinical and genetic analysis of 12 cases with molecularly confirmed OI type V from 12 unrelated families was performed. Significant clinical heterogeneity of the disease with the same molecular defect was detected. In six subjects (50%), there were no classic signs of OI type V (formation of a hyperplastic bone callus, calcification of the interosseous membrane and dislocation of the radial head). In all cases, the mutation occurred de novo.

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Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients

Zhou

Rooij

Laarschot

et al. 2020

Journal of Bone and Mineral Research

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Atypical femur fractures (AFFs), considered rare associations of bisphosphonates, have also been reported in patients with monogenic bone disorders without bisphosphonate use. The exact association between AFFs and monogenic bone disorders remains unknown. Our aim was to determine the prevalence of monogenic bone disorders in a Dutch AFF cohort. AFF patients were recruited from two specialist bone centers in the Netherlands. Medical records of the AFF patients were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole‐exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines. Copy number variations overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprises 60 AFF patients (including a pair of siblings), with 95% having received bisphosphonates. Fifteen AFF patients (25%) had clinical features of monogenic bone disorders. Eight of them (54%), including the pair of siblings, had a (likely) pathogenic variant in either PLS3, COL1A2, LRP5, or ALPL. One patient carried a likely pathogenic variant in TCIRG1 among patients not suspected of monogenic bone disorders (2%). In total, nine patients in this AFF cohort (15%) had a (likely) pathogenic variant. In one patient, we identified a 12.7 Mb deletion in chromosome 6, encompassing TENT5A. The findings indicate a strong relationship between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, but mainly in individuals with symptoms of these disorders. The high yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of these disorders stresses the importance of careful clinical evaluation of AFF patients. Although the relevance of bisphosphonate use in this relationship is currently unclear, clinicians should consider these findings in medical management of these patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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De novo and inherited pathogenic variants in collagen‐related osteogenesis imperfecta

Cited by 14 publications

References 29 publications

Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta

Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta

Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review

Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients

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