Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India

Abstract

BackgroundDyggve-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 inDYM. SMC2 is caused by variations inRAB33B. BothDYMandRAB33Bare important in intravesicular transport and function in the Golgi apparatus.MethodsDetailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirmDYMandRAB33Bvariants. Sanger sequencing of familial variants was done in all parents.Results24 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 eitherDYMorRAB33B. 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) inRAB33B. The majority of these have not been reported previously.ConclusionThis large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare ‘Golgipathies’.