Human Constitutional Tetrasomy 18p: A Case Study of Genotype - Phenotype Corelation

Abstract

Tetrasomy 18p is a chromosomal disorder observed due to the presence of isochromosome 18p in constitutional karyotype leading to a genomic imbalance. The commonly observed phenotypes are developmental delays, cognitive impairment, hypotonia, typical dysmorphic features, etc. anomalies. The present study was carried out in a previously reported case of tetrasomy 18p. The detection of constitutional chromosome anomaly in a patient is important for clinical diagnosis, prognosis, and genetic counselling. The detection of this chromosomal anomaly was an accidental finding in 2006. Karyotyping of proband and parents was already performed, where parents karyotyping was normal and isochromosome in proband was detected by M-FISH followed by M-BAND method. Quantitative Fluorescence-Polymerase Chain Reaction (QF-PCR) is being used by many laboratories for diagnosis of various aneuploidies. QF-PCR is rapid, economic, and can identify most chromosomal disorders diagnosed by conventional karyotyping. In addition to aneuploidy, including parental DNA samples helps identification of parental and origin and also meiotic origin of a chromosomal aberration. The STR (Short Tandem Repeat) marker D18S391 was used in QF-PCR analysis of the proband as well as her parents. Results were analyzed by using Gene Mapper V4.0 followed by calculation of Peak Height Ratio. The results revealed the maternal origin of extra copy of 18p in the proband. There are a total of 67 genes present on Chromosome 18p. Out of which some express phenotypic traits that can be linked to certain phenotypic features observed in the proband due to dosage effect. We have also analysed the possible role of imprinting in addition to dosage effect, as the extra copy of 18p genes are from the maternal side and one gene is reported to be imprinted. The automation in diagnosis of genetic disorders has been attempted using machine learning approach to get a better clue for the wet lab analysis. Facial phenotypic characterization of individuals is conducted using Face2Gene mobile application. It is an artificial intelligence based software that analyses the picture of a person's face, correlates it with the present database and gives output in terms of a list of around 30 possible syndromes for the given case which could be validated using relevant wet lab diagnostic techniques. To assess the accuracy of Face2Gene App in identifying the chromosomal disorder we assessed the sensitivity and specificity of the application. In order to validate the App, a well studied genetic condition was taken as a positive control. With ethical approval and informed consent, the facial pictures of known Down syndrome patients were obtained and analysed using this App. It was found to detect Down syndrome with high specificity. Similarly, when pictures of the proband were submitted the list of possible syndromes did not show tetrasomy 18p syndrome with high likelihood scores. The outcome explains that tetrasomy 18p does not include a specific signature phenotype like Down syndrome, more so due to mosaicism of karyotype in our proband.