Introduction: The armamentarium of newer genetic tools is expanding.  We present a case series where selecting the right test proved to be conclusive.

Diagnosis inapparent

a) A female infant presented with developmental delay, seizures, hearing-loss. The following tests were unyielding: newborn screening, neuroimaging, work-up for Krabbe-disease/ neuronal-ceroid-lipofuscinosis and clinical-exome. Whole-exome-sequencing (proband) at 4.5 years yielded autosomal-recessive condition, Epilepsy Hearing-Loss Mental-Retardation Syndrome (SPATA5gene).

b) A two-year old female presented with developmental delay, orofacial cleft, craniofacial dysmorphisms; the syndrome inapparent. Chromosomal-microarray (CMA) revealed pathogenic microdeletion (13q33-34).

Diagnosis apparent

a) A couple lost their 10-month male to suspected Niemann-Pick-disease (NPD). Presentation included neuroregression, splenohepatomegaly, recurrent jaundice. Serum sphingomyelinase was 25% of lower-limit-of-normal. Next-generation-sequencing (NGS) analysis of SMPD1 was unyielding twice. Uncertain diagnosis prompted the couple to abort their next pregnancy. The expired proband’s DNA was retrieved. Multiplex-ligation-probe-dependent-amplification (which can detect copy-number-variants, unlike NGS) yielded homozygous duplication in SMPD1, confirming NPD.

b) Two sisters suffering from skin peeling since birth, seizures, developmental delay, expired by 1.5-years. Suspecting autosomal recessive Mendelian-disorder-of-cornification, CMA was performed in the second sibling. Loss-of-heterozygosity in ELOVL4 responsible for Ichthyosis Spastic-Quadriparesis Mental-Retardation was detected. Proband’s DNA was unavailable. Retrospective parental Sanger-sequencing (ELOVL4) yielded pathogenic heterozygous variant in each.

c) An 18-month, female presented with developmental delay, pulmonary stenosis, craniofacial dysmorphisms reminiscent of Rasopathy spectrum. Clinical-exome yielded pathogenic variant in PTPN11 (Noonan-Syndrome).

Conclusion: The clinical scenario dictates the careful selection of the different genetic tools.