GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations

Genovesi, Maria Luce; Guadagnolo, Daniele; Marchionni, Enrica; Giovannetti, Agnese; Traversa, Alice; Panzironi, Noemi; Bernardo, Silvia; Palumbo, Pietro; Petrizzelli, Francesco; Carella, Massimo; Mazza, Tommaso; Pizzuti, Antonio; Caputo, Viviana

doi:10.1016/j.bone.2020.115803

Cited by 9 publications

(11 citation statements)

References 65 publications

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“…If the mutation decreases the expression of GDF5 protein or blocks the binding of GDF5 to the TGF-β receptor structural domain of BMPR1B, the related signaling pathway is downregulated, resulting in the development of short fingers; if the mutation increases the affinity of GDF5 for BMPR1B, symphalangism can occur. 9,17 In this patient, we detected the heterozygous mutation c.349delG in exon 1 of GDF5. As a result, the propeptide after codon 117 could not be translated correctly and was terminated after six amino acids (p.A117fs*6), causing GDF5 haploinsufficiency.…”

Section: Discussionmentioning

confidence: 68%

“…BMPR1B, the receptor for GDF5, is associated with the development of the proximo‐distal trend and joint formation. If the mutation decreases the expression of GDF5 protein or blocks the binding of GDF5 to the TGF‐β receptor structural domain of BMPR1B, the related signaling pathway is downregulated, resulting in the development of short fingers; if the mutation increases the affinity of GDF5 for BMPR1B, symphalangism can occur 9,17 . In this patient, we detected the heterozygous mutation c.349delG in exon 1 of GDF5.…”

Section: Discussionmentioning

confidence: 80%

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Frameshift Mutation in a Chinese Patient with Brachydactyly Type C Involving the Third Metacarpal: A Case Report

Bai

Chen

2022

Orthopaedic Surgery

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Brachydactyly is a common feature of congenital hand anomalies characterized by shortening of the phalanges and/or metacarpals. Mutation of growth differentiation factor-5 (GDF5) may result in loss of appearance and function in brachydactyly type C (BDC). Herein, we describe an 11 year-old Chinese BDC patient with significant shortening of the 1st, 2nd, 3rd, and 5th digits. Notably, according to the analysis of metacarpophalangeal pattern profiles, we do not think the 4th digit appears unaffected as usual. In this patient a novel heterozygous frameshift mutation was identified (c.349delG) causing termination of translation after translating six amino acids from codon 117 (p.A117fs*6). This mutation is located in the propeptide region of GDF5, causing GDF5 haploinsufficiency in BDC. Considering our results expanding the genetic spectrum of BDC-causing mutations, further molecular analysis to diagnose and reclassify isolated brachydactyly on the basis of genotype rather than phenotype is warranted.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 80%

Frameshift Mutation in a Chinese Patient with Brachydactyly Type C Involving the Third Metacarpal: A Case Report

Bai

Chen

2022

Orthopaedic Surgery

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“…Degenkolbe et al indicate that the superagonistic GDF5 variant shows faster and more efficient bone defect healing in patients with multiple synostoses syndrome using an animal model [ 39 ]. Given that different GDF5 pathogenic mutations are related to different clinical features, the depression of GDF5 may result in bone development defects, and overexpression causes excessive bone formation [ 40 ]. The current study suggests that SNP rsl43384 in GDF5 is associated with orthopedic CPSP.…”

Section: Discussionmentioning

confidence: 99%

The effect of common variants in GDF5 gene on the susceptibility to chronic postsurgical pain

Yan

Nie

et al. 2021

J Orthop Surg Res

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Background The growth differentiation factor 5 (GDF5) gene regulates the growth of neuronal axons and dendrites and plays a role in the inflammatory response and tissue damage. The gene may also be associated with chronic postsurgical pain. This study aimed to reveal the relationship between SNPs in the GDF5 gene and orthopedic chronic postsurgical pain in Han Chinese population based on a case-control study. Methods We genotyped 8 SNPs within GDF5 gene in 1048 surgical patients with chronic postsurgical pain as the case group and 2062 surgical patients who were pain free as the control group. SNP and haplotypic analyses were performed, and stratified analyses were conducted to determine the correlations between significant SNPs and clinical characteristics. Results Only rs143384 in the 5′UTR of GDF5 was identified as significantly associated with increased susceptibility to chronic postsurgical pain, and the risk of A allele carriers was increased approximately 1.35-fold compared with that of G allele carriers. Haplotypes AGG and GGG in the LD block rs143384-rs224335-rs739329 also showed similar association patterns. Furthermore, we found that rs143384 was significantly correlated with chronic postsurgical pain in the subgroup aged ≤ 61 years, subgroup with a BMI ≤ 26, subgroup with no-smoking or no pain history, and subgroup with a drinking history. Conclusion Our study provided supportive evidence that genetic variations in the GDF5 gene are potential genetic factors that can increase the risk of chronic postsurgical pain in the Han Chinese population, but further research is necessary to elucidate the underlying mechanism.

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“…Proband's DNA was analyzed by WES by using SureSelect Human All Exome V6 (Agilent Technologies, Santa Clara, CA, USA) following manufacturer instructions as previously described [6]. This is a combined shearing-free transposase-based library prep and target-enrichment solution, which enables comprehensive coverage of the entire exome.…”

Section: Whole Exome Sequencing (Wes)mentioning

confidence: 99%

Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies

Palumbo

Muro

Accadia³

et al. 2021

Genes

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Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting in the developmental age. To date, more than 1000 genes have been implicated in the etiopathogenesis of NNDs. Among them, AUTS2 (OMIM # 607270) encodes a protein involved in neural migration and neuritogenesis, and causes NNDs with different molecular mechanisms including copy number variations, single or multiple exonic deletion and single nucleotide variants. We describes a 9-year-old boy with global developmental delay, absent speech, minor craniofacial anomalies, hypoplasia of the cerebellar vermis and thinning of the corpus callosum, resulted carrier of the de novo AUTS2 c.1603_1626del deletion at whole exome sequencing (WES) predicted to cause the loss of eight amino acids [p.(His535_Thr542del)]. Notably, our patient is the first reported so far in medical literature carrying an in-frame deletion and the first in which absent language, hypoplasia of the cerebellar vermis and thinning of the corpus callosum has been observed thus useful to expand the molecular spectrum of AUTS2 pathogenic variants and to broaden our knowledge on the clinical phenotype associated.

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GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations

Cited by 9 publications

References 65 publications

Frameshift Mutation in a Chinese Patient with Brachydactyly Type C Involving the Third Metacarpal: A Case Report

Frameshift Mutation in a Chinese Patient with Brachydactyly Type C Involving the Third Metacarpal: A Case Report

The effect of common variants in GDF5 gene on the susceptibility to chronic postsurgical pain

Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies

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