Dr. D. K. Chopade President, Down Syndrome Care Association, India Presentation at IIDSC-2017 New Delhi 10/09/2017 Cytogenetic correlation of cardiac and non-cardiac anomalies in Down syndrome Dr. D. K. Chopade President, Down Syndrome Care Association, India Genetic Health & Research Centre, 7, Mahatmanagar, near ABB signal, Triambak Road, Nashik, Maharashtra

Introduction: It is the most common genetic disorder in the world Incidence: 1 in 1000 Types as per chromosomal abnormalities: Sr No Type of Down Syndrome Chromosomal abnormality Prevalence 1 Free Trisomy 21 Three separate copies of chromosome 21 94% 2 Translocation Down syndrome Extra copy of chromosome 21 is attached to other chromosomes like 21, 22, 13, 14 or 15 3.3% 3 Mosaic Down syndrome Some cells show normal 46 chromosomes, while others show extra 21 2.4%

Karyotype of a boy with 21;21 Robertsonian translocaton Down syndrome Karyotype of a boy with free trisomy 21 Down syndrome Karyotype of a girl with 14;21 Robertsonian translocation Down syndrome

The major cause of early mortality is- Congenital heart defect Clinical Features reported Sr No Principle features observed % 1 Hypotonia 80 2 Hyperflexible of joints 3 Excees skin on back of neck 4 Flat face 90 5 Slanted palpebral fissures 6 Abnormal auricles 60 7 Dysplasia of middle phalynx Sr No Major Congenital malformations observed % 1 CNS- Mental deficiency 100% 2 Cardiac- Atrioventricular defects Ventricular septal defects Patent Ductus arteriosus Atrial septal defects 40% 3 Gastro-intestinal abnormalities Tracheoesophageal fistula Duodenal atresia Pyloric stenosis Hirschprung disease Imperforate anus 12% 8 Dysplasia of pelvis 70 9 Simian crease 45 The major cause of early mortality is- Congenital heart defect

The aim of this study To establish the clinical and cytogenetic correlation in the individuals with Down’s syndrome Study Design Retrospective analysis 482 individuals with Down syndrome, Methods: clinical and cytogenetic evaluation Period-2003 to 2015 Place of study-Genetic and Health Research Centre, Nashik, India.

Results Table No: 1 Clinical Correlation with the different types of chromosomal abnormalities in Down’s syndrome (n=482 M:F- 1.4:1)- Types of CA M F Total Cardiac Anomalies Non-Cardiac Anomalies CA in parents (n=36) Free Trisomy 21 87.55% 249 173 422 186/422 (44.1%) 85/422 (20.1%) Not available RT (n= 36) 7.470% 21;21 12 07 19- 52.77% 9/19 (47.36%) 4/19 (21.1%) 45, XY, t(21;21)- 1 21;22 -- - 14;21 06 13- 36.11% 7/13 (53.85%) 3/13 (23.1%) 45, XX, t(14;21)- 3 45, XY, t(14;21)- 1 13;21   15;21 03 01 04- 11.11% 02/4 (50%) 00 45, XY, t(15;21)- 1 Mosaicism- 4.56% 10 22 03/10 (30%) No obvious CA 02 283 199 482 207/482 (42.9%) 92/482 (19.1%) M- Male, F- Female, RT- Robertsonian Translocation, CA- Chromosomal Abnormality

Results Table No 2: Various Congenital cardiac Anomalies observed No of cases % Chromosomal abnormalities Free trisomy RT Mosaic Atrioventricular Septal Defect 105 51 95/105 (90.5%) 10 (9.5%) - Ventricular Septal Defect 62 30 60/62 (96.7%) 2 (3.3%) Atrial Septal Defects 17 8 13/17 (76.5% 2 (11.7%) Patent Ductus Arteriosus 13/17 (76.5%) 3 (17.6%) 1 (5.9%) Tetralogy of Fallot 06 3 5/6 (83.3%) 1 (16.7%) Total 207 100 186/207 (89.85%) 18 RT- Robertsonian Translocation

Hirschprung’s disease Results Table No.3: Various Non-cardiac Anomalies Observed (Total Number- 92) Chromosomal abnormality Duodenal atresia Imperforate anus Hirschprung’s disease Total (92 cases) Free trisomy 21 (422) 36 21 17 74 (80.43%) t(21;21) +21 (19) 5 3 2 10 18 (19.56%) t(14;21) +21 (13) 1 7 t(15;21) +21 (4) - Mosaicism (22) 44 28 20 92

Main findings of our study Frequency of various chromosomal abnormalities observed- Free trisomy 21- 87.55% Robertsonian Translocation- 7.47% Mosaicism- 4.56% Male to Female ratio observed is 1.4:1 2 cases did not show any chromosomal abnormality The most common Robertsonian translocation found was – t(21;21) followed by t(14;21) Parents of children with Robertsonian translocation Down syndrome showed balanced Robertsonian translocation at a frequency of 16.7% (6/36)

CHD was observed in 42.95% of all cases with DS The most common cardiac anomaly observed is Atrioventricular septal defect in 51% cases Atrioventricular septal defect was observed with the highest frequency in translocation DS cases Chromosomal abnormalities in children of DS with cardiac defects- Free trisomy 21- 89.85% Robertsonian translocation- 8.70% Mosaicism- 1.45% Non-cardiac anomalies observed- Duodenal atresia in 9%, imperforate anus in 6% and Hirschprung disease in 4% cases of DS

Conclusion There is a close association between various types of chromosomal abnormalities and cardiac and non-cardiac malformations The extra genetic material on chromosome 21 playes a vital role in development of major congenital malformations All the children with Down syndrome should be investigated for the major cardiac and non-cardiac malformations

Thank you so much…… Dr. Dnyandeo Chopade Director and Consultant Medical Geneticist Genetic Health & Research Centre, Nashik Email- drchopade@Hotmail.com Mobile- + 91 9822885558