Article Text
PDF
Abstract
Background Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus.
Methods Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents.
Results 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously.
Conclusion This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare ‘Golgipathies’.
- Genetics, Medical
- Sequence Analysis, DNA
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Patients/patient families have consented for publication of photographs and investigations to be shared. An informed consent form is available for each family. The data that support the findings of this study are available on request.
Statistics from Altmetric.com
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Patients/patient families have consented for publication of photographs and investigations to be shared. An informed consent form is available for each family. The data that support the findings of this study are available on request.
Footnotes
Contributors KV and MB conceptualised and designed the study, analysed the data, and wrote and reviewed the manuscript. They will act as guarantors of this study. SGN, KMG, DN, GSB, SP, MN, SN, PR and GAU enrolled the patients, collected clinical and demographic details, contributed clinical samples, written informed consents, analysed the manuscript and provided valuable suggestions. KMG, DN and GSB were involved in the molecular and bioinformatic analyses of six samples. TSG was involved in the molecular analyses of the 18 samples and in the write-up of the laboratory protocol described in the manuscript. All authors have reviewed and approved the final manuscript. KV and MB agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding KMG, DN and GSB acknowledge the Department of Science and Technology (DST) and the Science and Engineering Research Board (SERB) (DST/SERB grant number: SB/SO/HS/005/2014) for funding the study.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.