Mitochondrial Encephalohepatopathy (MEH) is an autosomal recessive neurodevelopmental disorder usually accompanied by microcephaly, white matter changes, cardiac and hepatic failure. Here, we applied the whole-exome sequencing (WES) framework on a trio family data with unaffected non-consanguineous parents and proband (neonate girl) with this inherited disorder. A total of 2,928,402 variants were observed with 2,613,746 SNPs, 112,336 multiple nucleotide polymorphisms (MNPs), 72,610 insertions, 113,207 deletions and 16,503 mixed variants. These variations are responsible for 82,813,631 effects on various genomic regions. Our pipeline uncovered candidate gene mutations from these variants and retained a handful of 5,277 variants harboring 3,598 genes, out of which, 8 genes codes for non-coding RNA while 178 genes are those with high impact severity. Among these 178 variants, 125 are de-novo variants that are not previously reported in the ClinVar database. Consistent to previous studies, the leftover high impact severity genes are involved in encephalopathy, Leigh syndrome, Charcot–Marie–Tooth disease, global developmental disorder, seizures, spastic paraplegia, premature ovarian failure, mitochondrial myopathy-cerebellar, ataxia-pigmentary, retinopathy syndrome, ocular and retinal degeneration, deafness, intellectual disability, cardiofacioneurodevelopmental syndrome etc. All these clinical features were also observed in the patient studied. The current analysis highlights and expands the genetic architecture of the MEH phenotype. Furthermore, this pipeline on trio family data significantly broadens the concept of its usefulness as a first-tier diagnostic method in the detection of complex multisystem phenotypic disorders.