Application of whole exome sequencing in fetal cases with skeletal abnormalities

Cao, Juan; Chen, An'er; Tian, Li-Yun; Yan, Lulu; Li, Haibo; Zhou, Bihua

doi:10.1016/j.heliyon.2022.e09819

Cited by 4 publications

(2 citation statements)

References 32 publications

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“…However, all cases except OI-8 exhibited severe prenatal USG findings that indicated a high risk of fatality. Variants such as p.(Gly332Arg) in OI-27, p.(Gly428Cys) in OI-1, p.(Gly833Val) in OI-28, p.(Gly1076Ser) in OI-7, and p.(Gly1166Cys) in OI-29 in COL1A1 have been reported in the literature to be associated with severe prenatal ultrasound findings, despite being located outside the established lethal regions [8, 10, 32‒36]. Moreover, it has been demonstrated for the first time that variants such as p.(Gly338Val), p.(Gly779Val), p.(Gly1049Ser), p.(Asp1413Gly) in COL1A1 and p.(Gly346Cys) in COL1A2 , albeit outside the aforementioned lethal regions, are associated with severe OI type II in the perinatal period.…”

Section: Discussionmentioning

confidence: 99%

Association of Antenatal Evaluations with Postmortem and Genetic Findings in the Series of Fetal Osteogenesis Imperfecta

Senturk,

Gulec,

Sarac Sivrikoz

et al. 2024

Fetal Diagn Ther

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Introduction: Counseling Osteogenesis Imperfecta (OI) pregnancies is challenging due to the wide range of onsets and clinical severities, from perinatal lethality to milder forms detected later in life. Methods: Thirty-eight individuals from 36 families were diagnosed with OI through prenatal ultrasonography and/or postmortem clinical and radiographic findings. Genetic analysis was conducted on 26 genes associated with OI in these subjects that emerged over the past 20 years, while some genes were examined progressively, all 26 genes were examined in the group where no pathogenic variations were detected. Results: Prenatal and postnatal observations both consistently showed short limbs in 97%, followed by bowing of the long bones in 89%. Among 32 evaluated cases, all exhibited cranial hypomineralization. Fractures were found in 29 (76%) cases, with multiple bones involved in 18 of them. Genetic associations were disclosed in 27 families with 22 (81%) autosomal dominant and five (19%) autosomal recessive forms, revealing 25 variants in six genes (COL1A1, COL1A2, CREB3L1, P3H1, FKBP10, and IFITM5), including nine novels. Postmortem radiological examination showed variability in intra-family expression of CREBL3 and P3H1-related OI. Conclusion: Prenatal diagnosis for distinguishing OI and its subtypes relies on factors such as family history, timing, ultrasound, genetic and postmortem evaluation.

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Section: Discussionmentioning

confidence: 99%

Association of Antenatal Evaluations with Postmortem and Genetic Findings in the Series of Fetal Osteogenesis Imperfecta

Senturk,

Gulec,

Sarac Sivrikoz

et al. 2024

Fetal Diagn Ther

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“…Despite the numerous advances in WES technology, conclusions drawn from the majority of pilot studies are biased by small cohorts ( Cao et al, 2022 ; Yang et al, 2022 ) or are limited to highly selected cases or other certain conditions ( Liu et al, 2019 ; Lei et al, 2022 ). Further pilot studies involving different disorders, conditions, sample types, and analytic methods are necessary to expand our understanding in the application of WES on prenatal diagnosis and to establish the diagnostic yield of WES for all kinds of prenatal disorders.…”

Section: Introductionmentioning

confidence: 99%

Prenatal diagnosis of fetuses with ultrasound anomalies by whole-exome sequencing in Luoyang city, China

Wang,

Yin,

Chai

et al. 2024

Front. Genet.

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Background: There is a great obstacle in prenatal diagnosis of fetal anomalies due to their considerable genetic and clinical heterogeneity. Whole-exome sequencing (WES) has been confirmed as a successful option for genetic diagnosis in pediatrics, but its clinical utility for prenatal diagnosis remains to be limited.Methods: A total of 60 fetuses with abnormal ultrasound findings underwent karyotyping or chromosomal microarray analysis (CMA), and those with negative results were further subjected to WES. The identified variants were classified as pathogenic or likely pathogenic (P/LP) and the variant of uncertain significance (VUS). Pregnancy outcomes were obtained through a telephone follow-up.Results: Twelve (20%, 12/60) fetuses were diagnosed to have chromosomal abnormalities using karyotyping or CMA. Of the remaining 48 cases that underwent WES, P/LP variants were identified in 14 cases (29.2%), giving an additional diagnostic yield of 23.3% (14/60). The most frequently affected organ referred for prenatal WES was the head or neck system (40%), followed by the skeletal system (39.1%). In terms of pathogenic genes, FGFR3 was the most common diagnostic gene in this cohort. For the first time, we discovered five P/LP variants involved in SEC24D, FIG4, CTNNA3, EPG5, and PKD2. In addition, we identified three VUSes that had been reported previously. Outcomes of pregnancy were available for 54 cases, of which 24 cases were terminated.Conclusion: The results confirmed that WES is a powerful tool in prenatal diagnosis, especially for fetuses with ultrasonographic anomalies that cannot be diagnosed using conventional prenatal methods. Additionally, newly identified variants will expand the phenotypic spectrum of monogenic disorders and greatly enrich the prenatal diagnostic database.

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A De novo Mutation in the COL1A1 Gene Leading to Severe Osteogenesis Imperfecta: Case Report and Review of the Literature

Lu,

Tian,

Liu

et al. 2024

AJP Rep

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Introduction: Osteogenesis imperfecta(OI) is the most common monogenic inherited skeletal dysplasia disorder. Mutations in the COL1A1/ COL1A2 gene cause approximately 85-90% of OI. Studies of cases have demonstrated that Missense mutations are the primary cause of OI, with poor prognosis. Case Description: We report the case of a fetus with skeletal abnormalities and subcutaneous edema. Ultrasound imaging revealed suspected skeletal malformations, including hypoplastic long bones of all four limbs, poorly ossified calvarium, unrevealing nasal bones, and generalized subcutaneous edema. Whole-exome sequencing revealed a heterozygous mutation in COL1A1 [c.2174G>T/p.(G725V), NM_000088.3]. According to the ACMG guidelines, it was determined to be a pathogenic variant and identified as a de novo variant(PS2+PP3_Strong+PM2_Supporting), which has not been reported in the HGMD, gnomAD, Clinvar, or other databases. This variation causes a glycine to valine substitution at position 725, which is located within the Gly Xaa-Yaa repeat in the helical domain of the collagen molecule. Conclusions: The COL1A1 mutation [c.2174G>T/p.(G725V), NM_000088.3], is a novel pathogenic variant of severe OI. Our study expanded the OI COL1A1 gene variation profiles in the Chinese population and provided a theoretical foundation for prenatal diagnosis, genetic counseling, and obstetric management.

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Application of whole exome sequencing in fetal cases with skeletal abnormalities

Cited by 4 publications

References 32 publications

Association of Antenatal Evaluations with Postmortem and Genetic Findings in the Series of Fetal Osteogenesis Imperfecta

Association of Antenatal Evaluations with Postmortem and Genetic Findings in the Series of Fetal Osteogenesis Imperfecta

Prenatal diagnosis of fetuses with ultrasound anomalies by whole-exome sequencing in Luoyang city, China

A De novo Mutation in the COL1A1 Gene Leading to Severe Osteogenesis Imperfecta: Case Report and Review of the Literature

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