When was skeletal dysplasia discovered

Distinct skeletal disorders are identified by malformations of bone and cartilage during fetal development resulting in various anomalies in shape, structure, and size of bones of the skeleton.

Skeletal dysplasias are generally caused by mutations in a gene, which may be inherited from parents. Such conditions are often easily identified at birth due to their distinct physical features; however, some symptoms do not develop until the later years of childhood. Common characteristics include:. With the help of new tools and technology, the time spent searching for a diagnosis and determining which distinct type of a condition is present can be significantly reduced.

More than 50 different skeletal dysplasias may present in the prenatal period. Prenatally, the only way to make a conclusive diagnosis is to identify the causative gene variant. Determining a diagnosis is necessary for accurate counseling regarding pregnancy prognosis and recurrence risk in future offspring. Prenatal diagnosis commonly involves obtaining a small amount of amniotic fluid to analyze DNA in the fetal skin cells that have been sloughed off.

ARUP developed a 39 gene skeletal dysplasia panel targeted toward skeletal conditions that often manifest in the prenatal period to aid in the diagnosis and prognosis of such affected pregnancies. Both are frequently lethal within days or months after delivery. One of the most common survivable types of skeletal dysplasia is achondroplasia, which occurs in approximately 1 in 25, births; individuals are of normal intelligence and may have a normal lifespan.

However, skeletal dysplasia is a broad term that includes hundreds of conditions affecting bone and cartilage growth. Children born with a skeletal dysplasia may have differences in the size and shape of their legs, arms, trunk, or skull. Crit Rev Eukaryot Gene Expr ; 19 : — Stains JP, Civitelli R.

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Mutations in collagen genes were detected in cases 16—21 in the present study. Three fetuses cases 16—18 were diagnosed with osteogenesis imperfecta based on prenatal ultrasound, gross postnatal pathology, and X-ray examination Fig. Heterozygous mutations in COL2A1 were found in the other two fetuses cases 19 and 20 diagnosed with achondrogenesis type II.

The Sanger verification revealed that this mutation was new, and was not carried by the parents. In case 16, a heterozygous causative mutation c. In cases 17 and 18, two known pathogenic mutations were detected in the COL1A2 gene: c. GlySer and c. These mutations have been reported to be pathogenic mutations associated with osteogenesis imperfecta [ 24 , 25 , 26 , 27 , 28 ]. However, none of these mutations were detected in the parents, suggesting that these mutations are novel fetal mutations.

Mutations in COL2A1 disrupt the Gly-XY motif necessary for the formation of a triple helix structure, resulting in type II collagen over-modification, cellular retention and decreased secretion [ 29 , 30 ]. All these collagen-related mutations were new in the fetuses, and the parents were not mutation carriers.

The parents were advised to continue natural conception. Case The fetus with achondrogenesis. Case 21 was eventually diagnosed with fibrocartilage hyperplasia type II, which was caused by mutations in the COL11A2 gene.

The two COL11A2 mutations identified in the present study have only been previously identified once [ 31 ]. The Sanger sequencing verified that these phenotypically normal parents were mutation carriers. These parents were trying to conceive again with PGD. Fibroblast growth factors FGFs play an important role in endochondral osteogenesis and intramembranous osteogenesis.

Cells generally aggregate in several areas on osteophyte growth plates, and in the proximal dormant area, chondrocytes proliferate. Then, the chondrocytes differentiate into primary hypertrophic chondrocytes, and gradually become mature hypertrophic chondrocytes.

In the present study, seven fetuses with achondroplasia cases 23—29 were further examined with a combination of ultrasound, postnatal gross pathology, and X-ray. Based on these examinations, six of the fetuses were diagnosed with clinically fatal cartilage hypoplasia. The subsequent genetic analysis confirmed the fatal cartilage hypoplasia type I in six fetuses.

Cases 23—26 carried an identical mutation c. ArgCys , which is a common pathogenic mutation associated with lethal achondroplasia Fig.

In , Barkova et al. Similar findings were reported in by Chen et al. The study conducted by Rousseau et al. However, Xue et al. Another FGFR3 mutation, c. XS, , was identified in the present study, which has not previously been reported. This was a missense mutation that led to the false extension of protein translation. In case 27, the fetus was diagnosed with achondroplasia. GlyArg is the most common pathogenic mutation. The missense mutation c. GlyArg is identical to c.

GlyArg different transcripts. In , the study conducted by Bellus et al. For case 27, since the parents did not carry the mutation, it was considered a new mutation in the fetus. After genetic counseling, the parents were advised to continue to conceive naturally.

Case The fetus with fatal achondroplasia and fibroblast growth factor receptor 3 FGFR3 gene mutations. ThrPro in the FLNB gene carried by the fetus in case 30 is a missense mutation, which changes the amino acid at position from threonine to proline.

The sequence verification confirmed that neither of the parents carried the mutation, indicating that this was a novel mutation in the fetus. Therefore, the parents were advised to continue to conceive naturally. The fetus carried a heterozygous mutation in the EBP gene C. Herman et al. Among these 26 patients, 22 had EBP mutations. Among these 22 mutations, 13 mutations were de novo [ 37 ]. In the present study, a heterozygous EBP mutation a known causative mutation; c.

Whittock et al. However, neither of the parents carried the mutation. In the present study, the week-old female fetus presented with markedly short bones, ankle joint contracture, markedly asymmetric short lower limbs, and a flat face and nose bridge.

The severity of the phenotype was considered to be related to X chromosome inactivation, which is also known as lyonization. However, although targeted exome capture and sequencing have shown great advantages in disease gene identification and molecular diagnosis, some problems still needs to be immediately resolved. Fox example, exome sequencing focuses on the sequencing of exon regions. Thus, from the genome level, the information obtained was obviously incomplete.

Furthermore, information for promoter regions, enhancer regions and microRNA coding regions were certainly missed. Second, a large amount of data was obtained after exome sequencing.

The best method to perform an in-depth and accurate analysis of these data is the largest challenge faced at present by researchers worldwide. The deep mining of data needs to start from many aspects and perspectives, including studies at the transcription level, bioinformatics analysis, and functional genomics studies. In summary, the results of the present study suggest that the application of targeted gene sequencing technology can significantly improve the prenatal diagnosis of systemic skeletal abnormalities, allowing for a more comprehensive and useful prenatal genetic counseling guidance for parents.

Furthermore, the present study provides a theoretical basis for early intervention birth defect diagnoses and the assessment of fetal risk associated with subsequent pregnancies. In addition, the present study also provides further useful information for the continued development of skeletal dysplasia treatments based on target genes [ 32 ].

To date, mutations in genes are known to be associated with more than common skeletal dysplasias in humans [ 10 ]. However, genetic basis remains unknown in many additional skeletal diseases, especially local skeletal lesions, suggesting that new genes or non-genetic factors may cause these diseases.

All data generated or analysed during this study are included in this published article [and its supplementary information files]. Antenatal diagnosis of fetal skeletal malformation.