Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

Zhang, Jing; Hu, Huaying; Mu, Weihong; Yu, Man; Chen, Wenqi; Mi, Dongqing; Yang, Kai; Guo, Qing

doi:10.3389/fgene.2021.619948

Cited by 9 publications

(14 citation statements)

References 26 publications

(22 reference statements)

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“…It will provide some data for the early diagnosis of rare disease BS, and provide some ideas for future studies on genotypebased diagnosis and treatment strategies for BS. However, BS is a rare disease, the reported PLOD2 variant points are few and relatively concentrated, and the function of each domain of the LH2 protein is unclear (38). Therefore, the molecular genetic mechanism of BS which involves PLOD2 variant remains to be studied, and it is hoped that our research data can provide some reference for it.…”

Section: Discussionmentioning

confidence: 96%

“…LH peptides have two domains, the N-terminal and C-terminal, in which the C-terminal domain contains important catalytic residues of LH activity (20). Among the PLOD2 variants found to date, most are located between exons 12-19 and show obvious C-terminal aggregation (37,38). As the triple helix of the collagen molecule was assembled from the C-terminal to the N-terminal, a C-terminal variant could lead to more serious collagen structural instability and clinical phenotype (39).…”

Section: Discussionmentioning

confidence: 99%

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Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant

Wang

Ruan

et al. 2022

Front. Pediatr.

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BackgroundBruck syndrome (BS) is a rare autosomal recessive inherited osteogenesis imperfecta disease characterized by increased bone fragility and joint contracture. The pathogenic gene of type I BS is FKBPl0, whereas that of type II BS is PLOD2. No significant difference has been found in the clinical phenotype between the two types of BS. In this study, we performed genetic analysis of a BS pedigree caused by PLOD2 variant and studied the corresponding cellular function.MethodsSerum biochemistry, parathyroid hormone (PTH), 25-hydroxyvitamin D [25-(OH) D], osteocalcin, and 24-h urinary calcium levels of a family member with BS was assessed. The genes of the proband were analyzed by second-generation sequencing and exon capture techniques. Sanger sequencing was also performed for the suspected responsible variant of the family member. Wild- and variant-type lentivirus plasmids were constructed by gene cloning and transfected into HEK293T cells. Cell function was verified by real-time quantitative polymerase chain reaction, western blotting, and immunofluorescence detection.ResultsIn this pedigree, the proband was found to have a homozygous variant c.1856G > A (p.Arg619His) in exon 17 of PLOD2 (NM_182943.3). His consanguineous parents and sisters were p.Arg619His heterozygous carriers. The mRNA expression of PLOD2 in the constructed p.Arg619His variant cells was significantly upregulated, while the expression of PLOD2 and collagen I protein in the cell lysate was significantly downregulated. Immunofluorescence revealed that the wild-type PLOD2 was mainly located in the cytoplasm, and the expression of the PLOD2 protein after c.1856G > A variant was significantly downregulated, with almost no expression, aligning with the western blot results. The serum sodium, potassium, calcium, phosphorus, magnesium, alkaline phosphatase, PTH, 25-(OH) D, osteocalcin, and 24 h urinary calcium levels of the proband, his parents, and sisters were normal.ConclusionThrough gene and cell function analyses, PLOD2 Arg619His missense variant was preliminarily confirmed to cause BS by reducing protein expression.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant

Wang

Ruan

et al. 2022

Front. Pediatr.

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“…Osteogenesis imperfecta (OI) is a rare genetic disorder with an estimated prevalence between 1/13,500 and 1/9700(14), yet the most common form of primary osteoporosis in prenatal and perinatal circumstances [ 7 , 14 , 15 ]. There were numerous studies using molecular genetic techniques to achieve the prenatal diagnosis on OI [ 8 , 16 , 17 , 18 , 19 ]. A great deal of mutations in the COL1A1/2 genes, which confirms to the autosomal dominant pattern and contributed to a major part of OI cases, have been reported and indexed; as a result, researchers have begun to develop methods to assess the prognosis caused by specific types of mutations in recent years [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we established a trio whole-exome sequencing (trio-WES, meaning to submit “proband–father–mother” trios simultaneously for sequencing and mutation screening analysis) detection strategy, introduced it into the diagnosis of prenatal SD cases, and achieved a considerable detection efficiency [ 6 , 7 ]. We also reported a rare autosomal recessive OI case and identified a novel compound heterozygous variation in the PLOD2 gene, which encodes the lysine hydroxylase responsible for the proper cross-linking of type I collagen pro-fibrils [ 8 ]. Continuous effort has been made to better understand the various conditions of prenatal OI.…”

Section: Introductionmentioning

confidence: 99%

Prenatal Cases Reflect the Complexity of the COL1A1/2 Associated Osteogenesis Imperfecta

Yang

Liu

et al. 2022

Genes

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Introduction: Osteogenesis imperfecta (OI) is a rare mendelian skeletal dysplasia with autosomal dominant or recessive inheritance pattern, and almost the most common primary osteoporosis in prenatal settings. The diversity of clinical presentation and genetic etiology in prenatal OI cases presents a challenge to counseling yet has seldom been discussed in previous studies. Methods: Ten cases with suspected fetal OI were enrolled and submitted to a genetic detection using conventional karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES). Sanger sequencing was used as the validation method for potential diagnostic variants. In silico analysis of specific missense variants was also performed. Results: The karyotyping and CMA results of these cases were normal, while WES identified OI-associated variants in the COL1A1/2 genes in all ten cases. Six of these variants were novel. Additionally, four cases here exhibited distinctive clinical and/or genetic characteristics, including the situations of intrafamilial phenotypic variability, parental mosaicism, and “dual nosogenesis” (mutations in collagen I and another gene). Conclusion: Our study not only expands the spectrum of COL1A1/2-related OI, but also highlights the complexity that occurs in prenatal OI and the importance of clarifying its pathogenic mechanisms.

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“…Individual case reports [14][15][16][17][18] have described additional dysmorphic features, as reported in this child. The clinical outcomes and prognosis have been variable in reported cases, with some reported children dying soon after birth [19] while other patients have reportedly lived up to the third [20] or fourth [21] decade in life.…”

Section: Discussionmentioning

confidence: 99%

Arthrogryposis multiplex congenita in a child with congenital fractures: a case report

Dayasiri

Jayaweera

2022

J Med Case Reports

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Background Bruck syndrome is an exceedingly rare form of osteogenesis imperfecta, inherited autosomal recessively and presenting with the concurrence of bone fragility and congenital contractures of large joints. The disease usually progresses relentlessly to result in recurrent fractures, short stature, severe kyphoscoliosis, and susceptibility to recurrent respiratory tract infections. Case presentation The index child was a male newborn to healthy, nonconsanguineous, Sinhalese parents. The child had multiple contractures involving all large joints with pterigium formation in addition to congenital fractures involving left humerus and ulna at birth. The phenotypic features in this child were highly suggestive of Bruck syndrome. Genetic counseling was offered to the parents, although specific genetic testing could not be undertaken due to lack of resources. Bone and skin biopsy were not performed since only palliative care was possible. Over the course, he developed recurrent severe chest infections due to poor muscle tone, weak cough reflex, and pooling of secretions. Unfortunately, he succumbed at the age of 7 months following severe pneumonia. Conclusion The association of arthrogryposis with osteogenesis imperfecta is extremely rare and known as Bruck syndrome. Early diagnosis during the antenatal period is helpful in genetic counseling, assessment of severity, and exploration of therapeutic options

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Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

Cited by 9 publications

References 26 publications

Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant

Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant

Prenatal Cases Reflect the Complexity of the COL1A1/2 Associated Osteogenesis Imperfecta

Arthrogryposis multiplex congenita in a child with congenital fractures: a case report

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