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

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'.

Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: a model for the diagnosis and treatment of rare diseases in a developing country.

We report on a series of 514 consecutive diagnoses of skeletal dysplasia made over an 8-year period at a tertiary hospital in Kerala, India. The most common diagnostic groups were dysostosis multiplex group (n = 73) followed by FGFR3 (n = 49) and osteogenesis imperfecta and decreased bone density group (n = 41). Molecular confirmation was obtained in 109 cases. Clinical and radiographic evaluation was obtained in close diagnostic collaboration with expert groups abroad through Internet communication for difficult cases. This has allowed for targeted biochemical and molecular studies leading to the correct identification of rare or novel conditions, which has not only helped affected families by allowing for improved genetic counseling and prenatal diagnosis but also resulted in several scientific contributions. We conclude that (1) the spectrum of genetic bone disease in Kerala, India, is similar to that of other parts of the world, but recessive entities may be more frequent because of widespread consanguinity; (2) prenatal detection of skeletal dysplasias remains relatively rare because of limited access to expert prenatal ultrasound facilities; (3) because of the low accessibility to molecular tests, precise clinical-radiographic phenotyping remains the mainstay of diagnosis and counseling and of gatekeeping to efficient laboratory testing; (4) good phenotyping allows, a significant contribution to the recognition and characterization of novel entities. We suggest that the tight collaboration between a local reference center with dedicated personnel and expert diagnostic networks may be a proficient model to bring current diagnostics to developing countries.