Blended Phenotypes of Sexual Development Disorder and Coenzyme Q10 Deficiency, Together with a Sibling with Homozygous Variants in the AHI1 Gene.

Introduction: In consanguineous marriages, different homozygous variants in a single gene may occur in the same family. This may lead to blended phenotypes. This study presents a family in which different rare mechanisms come together as a result of consanguineous marriage. Primary coenzyme Q10 deficiency is a very rare disease that occurs due to homozygous or compound heterozygous variants in the COQ4 gene.

Case presentation: A 2-year-old proband with a blended phenotype with sex development disorder and coenzyme Q (CoQ) 10 deficiency has psychomotor retardation, dysmorphic findings, hypotonia, micropenis, and bilateral cryptorchidism. The patient's cytogenetic analysis results were compatible with SRY-positive 46,XX sex reversal disease. In the subsequent whole-exome analysis, a c.437T>G (Phe146Cys) missense homozygous probable pathogenic variant was detected in the 5th exon of the COQ4 gene (NM_016035) that explains other clinical findings. The brother of the index was previously deceased due to hydrocephalus and had a nonsense homozygous variant c.1051C>T p.(Arg351*) in the 7th exon of the AHI1 gene (NM_001134830).

Discussion: Alterations in exons 5-7 of the COQ4 gene manifest early in life, resulting in neonatal fatality and a more pronounced clinical trajectory. Conversely, mutations occurring in exons 1-4 emerge later and exhibit a less severe clinical progression. Interestingly, the c.437T>G variant within exon 5 of the COQ4 gene induces comparatively milder clinical symptoms, deviating from the documented cases in the literature. To our knowledge, there is no other reported case in the literature with a blended phenotype of a sexual development anomaly and primary CoQ10 deficiency.