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.

Keywords: ASPM; CTNS; consanguineous parents; dual molecular diagnoses; nephropathic cystinosis; primary microcephaly; recessive inheritance.

Figure 1

(A–C) Pictures of the patient at 2 years, 6 years, and 9 years of age, respectively, showing no relevant dysmorphisms besides microcephaly. Closed eyes point to photophobia. (D) Four-generation pedigree of family showing multiple consanguineous unions. Proband’s parents are first cousins and her mother was also born to consanguineous parents. (E) Brain nuclear magnetic resonance showing parenchyma with volumetric decrease and lissencephaly.

Figure 2

Sequence electropherograms of the trio for both variants. (A) c.4174C>T in the ASPM gene in homozygous state in the patient and heterozygous state in her parents. (B) c.382C>T in the CTNS gene in homozygous state in the patient and heterozygous state in her parents.