OBJECTIVE: To explore the genetic basis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome. METHODS: Whole exome sequencing and Sanger sequencing were carried out to detect potential pathogenic variants associated with the syndrome. The function of candidate variant was verified by Western blotting. RESULTS: A novel homozygous variant, c.1222delG of the DYM gene was detected in the two affected siblings, for which both parents were heterozygous carriers. The variant has caused replacement of Asp by Met at amino acid 408 and generate a premature stop codon p.Asp408Metfs*10. Western blotting confirmed that the variant can result in degradation of the mutant DYM protein, suggesting that it is a loss of function variant. CONCLUSION The homozygous c.1222delG frameshift variant of the DYM probably underlay the Dyggve-Melchior-Clausen syndrome in the two affected siblings. Above findings has enabled clinical diagnosis and genetic counseling for the family.
China ; Dwarfism/genetics* ; Humans ; Intellectual Disability ; Osteochondrodysplasias/genetics* ; Pedigree

Child ; Humans ; Karyotyping ; Male ; Osteochondrodysplasias ; classification ; diagnosis ; genetics

Humans ; East Asian People ; Genetic Profile ; Mutation ; Osteochondrodysplasias/genetics*

Cochlear Implantation ; Cochlear Implants ; Forehead/abnormalities* ; Humans ; Mutation ; Osteochondrodysplasias/genetics*

The transient receptor potential vanilloid 4 (TRPV4) cation channel, a member of the TRP vanilloid subfamily, is expressed in a broad range of tissues where it participates in the generation of Ca2+ signals and/or depolarization of the membrane potential. Regulation of TRPV4 abundance at the cell surface is critical for osmo- and mechanotransduction. Defects in TRPV4 are the cause of several human diseases, including brachyolmia type 3 (MIM:113500) (also known as brachyrachia or spondylometaphyseal dysplasia Kozlowski type [MIM:118452]), and metatropic dysplasia (MIM:156530) (also called metatropic dwarfism or parastremmatic dwarfism [MIM:168400]). These bone dysplasia mutants are characterized by severe dwarfism, kyphoscoliosis, distortion and bowing of the extremities, and contractures of the large joints. These diseases are characterized by a combination of decreased bone density, bowing of the long bones, platyspondyly, and striking irregularities of endochondral ossification with areas of calcific stippling and streaking in radiolucent epiphyses, metaphyses, and apophyses. In this review, we discuss the potential effect of the mutation on the regulation of TRPV4 functions, which are related to human diseases through deviated function. In particular, we emphasize how the constitutive active TRPV4 mutant affects endochondral ossification with a reduced number of hypertrophic chondrocytes and the presence of cartilage islands within the zone of primary mineralization. In addition, we summarize current knowledge about the role of TRPV4 in the pathogenesis of several diseases.
Humans ; *Mutation ; Osteochondrodysplasias/*genetics ; Osteogenesis/genetics ; TRPV Cation Channels/chemistry/*genetics/metabolism

OBJECTIVES: To study the clinical features and fibroblast growth factor receptor 3 (FGFR3) gene mutations of children with achondroplasia (ACH) through an analysis of 17 cases. METHODS: A retrospective analysis was performed on the clinical data and FGFR3 gene detection results of 17 children with ACH who were diagnosed from January 2009 to October 2021. RESULTS: Of the 17 children with ACH, common clinical manifestations included disproportionate short stature (100%, 17/17), macrocephaly (100%, 17/17), trident hand (82%, 14/17), and genu varum (88%, 15/17). The common imaging findings were rhizomelic shortening of the long bones (100%, 17/17) and narrowing of the lumbar intervertebral space (88%, 15/17). Major complications included skeletal dysplasia (100%, 17/17), middle ear dysfunction (82%, 14/17), motor/language developmental delay (88%, 15/17), chronic pain (59%, 10/17), sleep apnea (53%, 9/17), obesity (41%, 7/17), foramen magnum stenosis (35%, 6/17), and hydrocephalus (24%, 4/17). All 17 children (100%) had FGFR3 mutations, among whom 13 had c.1138G>A hotspot mutations of the FGFR3 gene, 2 had c.1138G>C mutations of the FGFR3 gene, and 2 had unreported mutations, with c.1252C>T mutations of the FGFR3 gene in one child and c.445+2_445+5delTAGG mutations of the FGFR3 gene in the other child. CONCLUSIONS This study identifies the unreported mutation sites of the FGFR3 gene, which extends the gene mutation spectrum of ACH. ACH is a progressive disease requiring lifelong management through multidisciplinary collaboration.
Achondroplasia/genetics* ; Child ; Humans ; Mutation ; Osteochondrodysplasias/genetics* ; Receptor, Fibroblast Growth Factor, Type 3/genetics* ; Retrospective Studies

OBJECTIVE: To explore the molecular basis for a pedigree affected with spondyloepiphyseal dysplasia congenita (SEDC). METHODS: The proband was subjected to whole exome sequencing. Suspected variant was verified by Sanger sequencing. RESULTS: All patients from the pedigree were found to carry a novel missense variant c.1394G>C (p.Gly465Ala) of the COL2A1 gene. The variant was not reported previously. Provean, Polyphen-2 and Mutation Taster software predicted that the variant is highly likely to be pathogenic. CONCLUSION The c.1394G>C (p.Gly465Ala) variant of the COL2A1 gene probably underlies the SEDC in this pedigree.
Asian Continental Ancestry Group ; Collagen Type II ; genetics ; Humans ; Osteochondrodysplasias ; congenital ; genetics ; Pedigree

OBJECTIVE: To explore the clinical and genetic characteristics of a child with frontometaphyseal dysplasia 1 (FMD1) due to variant of FLNA gene. METHODS: Clinical phenotype of the patient was analyzed. Whole exome sequencing (WES) was carried out to detect pathogenic genetic variants. Sanger sequencing was used to verify the result in his parents. RESULTS: The 2-year-and-9-month-old boy presented with facial dysmorphism (supraorbital hyperostosis, down-slanting palpebral fissure and ocular hypertelorism), skeletal deformities (bowed lower limbs, right genu valgum, left genu varus, slight deformity of index and middle fingers, and flexion contracture of little fingers). He also had limited left elbow movement. High-throughput sequencing revealed that he has carried a de novo heterogeneous c.3527G>A (p.Gly1176Glu) missense variant of the FLNA gene. The same variant was found in neither parent. CONCLUSION The clinical manifestations of FMD1 such as joint contracture and bone dysplasia can occur in infancy and deteriorate with age, and require long-term follow-up and treatment. Above finding has expanded the spectrum of FLNA gene variants.
Child ; Filamins/genetics* ; Forehead/abnormalities* ; Humans ; Infant ; Male ; Osteochondrodysplasias/genetics* ; Phenotype ; Whole Exome Sequencing

BACKGROUNDMultiple epiphysis dysplasia (MED) is a common skeletal dysplasia with a significant locus heterogeneity. In the majority of clinically defined cases, mutations have been identified in the gene encoding cartilage algometric matrix protein (COMP).

METHODSFive patients were included in the study. Linkage analysis and mutation analysis of the COMP gene were conducted in the patients and their family members.

RESULTSWe have identified a novel mutation in axon 14 of COMP gene in the family.

CONCLUSIONSThis mutation produced a severe MED phenotype with marked short stature, early onset osteoarthritis, and remarkable radiographic changes. Our results extended the range of disease-causing mutations in COMP gene and contributed more information about relationship between mutations and phenotype.

Adolescent ; Asian Continental Ancestry Group ; Cartilage Oligomeric Matrix Protein ; genetics ; Female ; Humans ; Male ; Osteochondrodysplasias ; genetics ; Pedigree ; Point Mutation ; genetics

OBJECTIVEWolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystem clinical manifestations. Here we describe a Chinese boy affected by WRS. Genetic testing of his EIF2AK3 gene was performed in order to elucidate molecular variations and subsequently to provide credible genetic counseling for prenatal diagnosis in his family.

METHODBased on analysis of a nine-year-old boy's clinical symptoms associated with biochemical examination and imaging, the diagnosis of WRS was therefore made. Genomic DNAs were extracted from peripheral blood leukocytes from the boy and his parents with their informed consent for genetic studies. All EIF2AK3 exons and intron-exon boundaries were amplified by Touch-down polymerase chain reaction (Touch-down PCR) and sequenced.

RESULTDirect sequencing of PCR products revealed the presence of a heterozygous T insertion (c.1408_1409insT) in exon 8 of the EIF2AK3 gene leading to frameshifting and termination, and another heterozygous T to A exchange (c.1596T > A) in exon 9 of the EIF2AK3 gene resulting in nonsense C532X mutation.

CONCLUSIONCombining mutation screening of EIF2AK3 gene with clinical manifestations and effective examination may provide a reliable diagnostic method for patients. In this research, two novel mutations identified in the Chinese boy locate in the catalytic domain of the EIF2AK3 gene, disrupting the ability of autophosphorylation, leading to the truncated proteins that are unable to phosphorylate the natural substrate, which are responsible for the phenotype of Wolcott-Rallison syndrome.

Child ; Diabetes Mellitus, Type 1 ; genetics ; Epiphyses ; abnormalities ; Humans ; Male ; Mutation ; Osteochondrodysplasias ; genetics ; eIF-2 Kinase ; genetics