12q21 Microdeletion in a fetus with Meckel syndrome involving CEP290/MKS4.

Abstract We report on a fetus with Meckel syndromediagnosed during the 21st gestational week, hydrocephalusand bilateral hyperechogenic kidneys were then detected on ultrasonography. Fetal pathological examination showed facial dysmorphism, occipital meningoencephalocele, characteristic renal cysts, mild hepatic ductal dysplasia, hydrocephalusin association with extreme cerebellar vermishypoplasia and brainstem anomalies. Molecular and cytogenetic analysis identified a paternally inherited CEP290 / MKS4 (MIM 611134 ) (12q21) nonsense mutationand a maternal 12q21 microdeletion. Two cases with such a mechanism have previously been described in the literature, one of them involves an inherited microdeletion. The observation of such cases highlights the existence of a pathogenic mechanism which involves deletion and point mutation, and illustrates how homozygosity can hide hemizygositywhen usual sequencing methods are used. The identification of hemizygosityenables to determine precisely the molecular mechanism and to understand some phenotypic variations. As they act as complete loss of function allele, deletions might give indication on the severity of the associated point mutation. This clinical report highlights the importance of fetal pathology following termination of pregnancies in order to guide molecular analysis and the potential role of cytogenetic cryptic disorders in autosomal recessive disease. The use of polymorphic marker analysis in association with FISH or arrayCGH provided an accurate identification of molecular mechanisms, accurate genetic counseling and optimized strategy for next pregnancies or preimplantation diagnosis.