Recurrent benign copy number variants & issues in interpretation of variants of unknown significance identified by cytogenetic microarray in Indian patients with intellectual disability.

Background & objectives: Cytogenetic microarray (CMA) is now recommended as a first-tier clinical diagnostic test in cases with idiopathic intellectual disability and/or developmental delay (ID/DD). Along with clinically relevant variants, CMA platforms also identify variants of unknown significance (VUS). This study was done to look for utility and various issues in interpretation of copy number variants (CNVs) in Indian patients with ID/DD. Methods: The CMA was performed in 86 Indian patients with idiopathic ID/DD with or without dysmorphic features. CNV was reported if copy number gain was >400 kb in size and copy number loss was > 200 kb in size. Results: Pathogenic CNVs were found in 18 of 86 (20.9%) patients. One large (14 Mb size) de novo heterozygous copy number gain was found in one patient. VUS (total 31) were present in 17 of 86 (19.7%) patients. Five novel recurrent benign CNVs were also present in our patients. Interpretation & conclusions: Our findings highlight the difficulties in interpretation of CNVs identified by CMA. More Indian data on VUS and recurrent benign CNVs will be helpful in the interpretation of CMA in patients with ID/DD.

Newborn Screening for Congenital Hypothyroidism, Galactosemia and Biotinidase Deficiency in Uttar Pradesh, India.

Objective: To assess feasibility and recall rates for newborn screening for congenital hypothyroidism, galactosemia and biotinidase deficiency in a predominantly rural and inner city population in and around the city of Lucknow in Uttar Pradesh, India. Design: Prospective observational study. Setting: Two tertiary-care and 5 district hospitals in and around Lucknow. Participants: All babies born in above hospitals during the study period. Methods: Heel prick samples were collected after 24 hours of life. Dried blood spot TSH, total galactose and biotinidase were assayed by immunofluorometry. Age related cut-offs were applied for recall for TSH. For galactosemia and biotinidase deficiency, manufacturer-suggested recall cut-offs used initially were modified after analysis of initial data. Main outcome measure: Recall rate for hypothyroidism, galactosemia and biotinidase deficiency. Results: Screening was carried out for 13426 newborns, 73% of all deliveries. Eighty-five percent of those recalled for confirmatory sampling responded. Using fixed TSH cut off of 20 mIU/L yielded high recall rate of 1.39%, which decreased to 0.84% with use of age-related cut-offs. Mean TSH was higher in males, and in low birth weight and vaginally delivered babies. Eleven babies had congenital hypothyroidism. Recall rates with modified cut-offs for galactosemia and biotinidase deficiency were 0.32% and 0.16%, respectively. Conclusion: An outreach program for newborn screening can be successfully carried out in similar socio-cultural settings in India. For hypothyroidism, the high recall rate due to early discharge was addressed by age-related cut-offs.