Result Of Karyotyping in Pediatric Patients With Congenital Anomalies and Developmental Delay

Chromosomal abnormalities are the leading cause of congenital anomalies with or without neurodevelopmental delay. It is increasing in incidence worldwide and occurs in 10-15% of pregnancies and contributes to 50-70% of spontaneous abortions. The genetic and congenital anomalies are higher in Sub-Saharan Africa by 20% than industrialized countries. Developmental delay (DD) is a measurable lag in achieving the age-related developmental milestones in young children. This could affect one domain (cognitive, motor, speech and language or social) or more than one domain which is global developmental delay. Global Developmental Delay affects 1-3% of children, and the prevalence of intellectual disabilities is estimated to be 18.3/1000 child and adolescent population.

There is limited data of birth prevalence of chromosomal abnormalities in the middle east and Africa. A meta-analysis of 66 articles with 52,569 congenital anomalies cases through Africa showed that the pooled proportion of chromosomal disorders among births with congenital anomalies in Africa is 8.94%, with highest prevalence in North African area than than the other African regions, compared to 12% in the USA. This may indicate underestimation due to limited resources and diagnostic tools in developing countries. This may also contribute to the fact that prevalence in the Middle East and Africa was between 20-30/1000 live births while it was 45-50/1000 live births in developed countries.

Prenatal diagnosis plays an important role in early detection of high-risk infants with congenital anomalies. Cytogenetics tests including karyotyping and Chromosomal Microarray (CMA) are effective prenatal genetic techniques to identify fetal anomalies. This leads to improvement of clinical outcome and performing appropriate genetic counselling. Unbalanced complex chromosomal arrangements (CCRs) is a rare rearrangement that involves three or more chromosomal break points, which mostly is de Novo but can be familial. Carriers of unbalanced CCRs may have Developmental delay and Congenital anomalies while carriers of the balanced type may have recurrent abortions and give birth to children with unbalanced CCRs.

The positive diagnostic yield of G-banded karyotyping with its inability to detect chromosomal abnormalities less than 10 Mb was 7.4% after exclusion of Down Syndrome detection, compared CMA in detecting chromosomal abnormalities in patients with unexplained developmental delay, Autistic spectrum disorders and multiple congenital anomalies which is 15-20%. This due to the high resolution of CMA and ability to detect smaller chromosomal aberrations. There was a high association between presence of hypotonia and diagnostic karyotyping (p.value=<0.001) (8), so despite the superiority of CMA in detecting small deletions and duplications it is recommended to reserve karyotyping for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

Another evidence which leads to recommendation to make CMA is first tier test for with developmental delay, intellectual disability, autism spectrum disorder, and/or multiple congenital anomalies, that the prevalence of congenital anomalies caused by microdeletions and duplications is about 1.2% compared to 0.2% caused by trisomies (21,13,18). CMA is cost-effective in diagnosing Developmental delay and Congenital anomalies than karyotyping as well as when testing the parents in case of copy number variant of unknown significance, but its use is limited by its higher cost. Karyotyping remains a test with a reasonable diagnostic yield for countries with limited resources. Further genetic tests may be required to diagnose patients where karyotyping and CMA fails to detect a chromosomal abnormality or a pathologic copy number of variants. This includes whole exome sequencing (WES) and targeted gene panels for intellectual disabilities which includes 1,252 genes. Leite A, et al. found a diagnostic rate of 42,3% when using the three diagnostic methods of karyotyping, CMA and WES.

G-banded Karyotyping and molecular karyotyping (CMA) may impact the clinical outcome of the patient in many aspects, this includes reaching a diagnosis, predicting outcome and level of care and multidisciplinary team assigned for managing the affected patients. It is mandatory to establish an effective cytogenetic-diagnostic facility beside well-trained genetic counsellors. This is in addition to developing a local registry system for congenital anomalies. On the other hand, parents testing and prenatal counselling or antenatal genetic testing in cases of balanced chromosomal rearrangements carriers is mandatory towards preventing recurrence.