Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review

Abstract

The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis. WES revealed two pathogenic and homozygous variants: a c.4174C>T variant in the ASPM gene and a c.382C>T variant in the CTNS gene, explaining the complex phenotype. The literature review showed that most of the patients harboring two variants in recessive disease genes are born to consanguineous parents. To the best of our knowledge, the patient herein described is the first one harboring pathogenic variants in both the ASPM and CTNS genes. These findings highlight the importance of searching for MPV in patients with complex phenotypes investigated by genome-wide testing methods, especially for those patients born to consanguineous parents.

An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report

“…The concept of multilocus pathogenic variations (MPV) is relatively new, corresponding to the occurrence of two or more monogenic disorders in the same individual, which leads to complex phenotypes difficult to identify only by clinical or biochemical tests ( Baltaci et al, 2021 ; Correia-Costa et al, 2022 ; Herman et al, 2022 ). Since the advent of genome/exome sequencing, MPVs have been identified in 1.4% to 7.2% of patients with rare diseases ( Yang et al, 2013 , 2014 ; Posey et al, 2017 ; Correia-Costa et al , 2022 ). For autosomal recessive disorders, homozygous MPVs can reach up to 29% of patients in populations that present high rates of consanguineous marriage ( Mitani et al, 2021 ).…”