A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review

Faryal, Sanam; Farooq, Muhammad; Abdullah, Uzma; Ali, Zafar; Saadi, Saadia Maryam; Ullah, Farid; Khan, Kamal; Sarwar, Yasra; Sher, Muhammad; Chopra, A.; Tommerup, Niels; Baig, Shahid Mahmood

doi:10.1016/j.ejmg.2021.104226

Cited by 5 publications

(5 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Baghdadi et al, 2019 reported a disequilibrium in the promoter of GDF5 , which was hypermethylated in patients with DDH [ 23 ]. Polymorphisms in GDF5 are also studied in association with various types of skeletal dysplasia (e.g., chondrodysplasia or brachydactyly) and osteoarthritis, which is frequently preceded by untreated DDH [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip

Harsanyi

Zamborský

Krajčíová

et al. 2021

Genes

View full text Add to dashboard Cite

Background: Developmental dysplasia of the hip (DDH) is one of the most prevalent skeletal disorders. DDH is considered a pathologic condition with polygenic background, but environmental and mechanic factors significantly contribute to its multifactorial etiology. Inheritance consistent with autosomal dominant type has also been observed. Single-nucleotide polymorphisms (SNPs) in various genes mostly related to formation of connective tissue are studied for a possible association with DDH. Methods: We genotyped three SNPs, rs1800796 located in the promoter region of the IL6 gene, rs143383 located in the 5′ untranslated region (UTR) of the GDF5 gene and rs726252 located in the fifth intron of the PAPPA2 gene. The study consisted of 45 subjects with DDH and 85 controls from all regions of Slovakia. Results: Association between DDH occurrence and studied genotypes affected by aforementioned polymorphisms was confirmed in the case of rs143383 in the GDF5 gene (p = 0.047), where the T allele was over-expressed in the study group. Meanwhile, in the matter of IL6 and PAPPA2, we found no association with DDH (p = 0.363 and p = 0.478, respectively). Conclusions: These results suggest that there is an association between DDH and GDF5 polymorphisms and that the T allele is more frequently presents in patients suffering from DDH.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip

Harsanyi

Zamborský

Krajčíová

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…BMP antagonists, such as NOGGIN (NOG), inhibit GDF5 activity and GDF5‐induced signal transduction by blocking the receptor‐binding site of GDF5 4 . A variant of GDF5 is associated with various genetic diseases, such as osteogenesis imperfecta and chondrodysplasia 5–12 . Some loss‐of‐function GDF5 variants result in reduced osteogenesis or abnormal bone development, such as brachydactyly (BD), whereas some gain‐of‐function GDF5 variants cause proximal symphalangism (SYM1, OMIM #185800) and multiple‐synostoses syndrome 2 (SYNS2, OMIM #610017).…”

Section: Introductionmentioning

confidence: 99%

“… 4 A variant of GDF5 is associated with various genetic diseases, such as osteogenesis imperfecta and chondrodysplasia. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 Some loss‐of‐function GDF5 variants result in reduced osteogenesis or abnormal bone development, such as brachydactyly (BD), whereas some gain‐of‐function GDF5 variants cause proximal symphalangism (SYM1, OMIM #185800) and multiple‐synostoses syndrome 2 (SYNS2, OMIM #610017). BD is classified into five types (A–E) according to the affected phalanges, and type A comprises three sub‐types (A1–A3).…”

Section: Introductionmentioning

confidence: 99%

A missense GDF5 variant causes brachydactyly type A1 and multiple‐synostoses syndrome 2

Li,

Liang,

Wang

et al. 2023

JOR Spine

View full text Add to dashboard Cite

ObjectiveThis study aimed to identify the molecular defects and clinical manifestations in a Chinese family with brachydactyly (BD) type A1 (BDA1) and multiple‐synostoses syndrome 2 (SYNS2).MethodsA Chinese family with BDA1 and SYNS2 was enrolled in this study. Whole‐exome sequencing was used to analyze the gene variants in the proband. The sequences of the candidate pathogenic variant in GDF5 was validated via Sanger sequencing. I‐TASSER and PyMOL were used to analyze the functional domains of the corresponding mutant proteins.ResultsThe family was found to have an autosomal‐dominantly inherited combination of BDA1 and SYNS2 caused by the S475N variant in the GDF5 gene. The variant was located within the functional region, and the mutated residue was found to be highly conserved among species. Via bioinformatic analyses, we predicted this variant to be deleterious, which perturb the protein function. The substitution of the negatively charged amino acid S475 with the neutral N475 was predicted to disrupt the formation of salt bridges with Y487 and impair the structure, stability, and function of the protein, consequently, the abnormalities in cartilage and bone development ensue.ConclusionsA single genetic variant (S475N) which disrupt the formation of salt bridges with Y487, in the interface of the antagonist‐ and receptor‐binding sites of GDF5 concurrently causes two pathological mechanisms. This is the first report of this variant, identified in a Chinese family with BDA1 and SYNS2.

show abstract

“…The index and middle fingers show hyperphalangism and their most proximal phalanges have abnormal configuration lending to ulnar deviation. The thumb metacarpals are slightly short GDF5 601,146 [ 17 ] BDD 113,200 Stub thumbs (short distal phalanges of the thumbs). The big toes may be similarly affected HOXD13 142,989 [ 18 ] BDE1 113,300 Short metacarpal IV, with/without short metatarsal IV (possible involvement of an isolated metatarsal) HOXD13 142,989 [ 18 ] BDE2 613,382 Short metacarpals IV and V (and metatarsals) with short distal phalanx of the thumb PTHLH 168,470 [ 19 ] BDE3 None Short metacarpals without phalangeal involvement None None [ 20 ] …”

Section: Introductionmentioning

confidence: 99%

“…According to the Bell classification, heritable isolated BDs have been classified into subtypes A to E according to their patterns of skeletal involvement [3]. Clinical features and pathogenic genes of isolated BDs are listed in Table 1 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Brachydactyly type B1 (BDB1, OMIM 113,000) is the most severe form of brachydactyly and is characterized by shortening or hypoplasia of the distal and middle phalanges of digits 2 through 5 with or without nail dysplasia, fusion of the middle and distal phalanges, variable degrees of distal and proximal symphalangism, and a broad or bifid thumb.…”

Section: Introductionmentioning

confidence: 99%

A novel variant in the ROR2 gene underlying brachydactyly type B: a case report

et al. 2022

View full text Add to dashboard Cite

Background Brachydactyly type B is an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails and can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is the most severe form of brachydactyly and is caused by truncating variants in the receptor tyrosine kinase–like orphan receptor 2 (ROR2) gene. Case presentation Here, we report a five-generation Chinese family with brachydactyly with or without syndactyly. The proband and her mother underwent digital separation in syndactyly, and the genetic analyses of the proband and her parents were provided. The novel heterozygous frameshift variant c.1320dupG, p.(Arg441Alafs*18) in the ROR2 gene was identified in the affected individuals by whole-exome sequencing and Sanger sequencing. The c.1320dupG variant in ROR2 is predicted to produce a truncated protein that lacks tyrosine kinase and serine/threonine- and proline-rich structures and remarkably alters the tertiary structures of the mutant ROR2 protein. Conclusion The c.1320dupG, p.(Arg441Alafs*18) variant in the ROR2 gene has not been reported in any databases thus far and therefore is novel. Our study extends the gene variant spectrum of brachydactyly and may provide information for the genetic counselling of family members.

show abstract

A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review

Cited by 5 publications

References 20 publications

Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip

Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip

A missense GDF5 variant causes brachydactyly type A1 and multiple‐synostoses syndrome 2

A novel variant in the ROR2 gene underlying brachydactyly type B: a case report

Contact Info

Product

Resources

About