Fetal Phenotyping and Whole Exome Sequencing for 12 Egyptian Families With Serine Biosynthesis Defect: Novel Clinical and Allelic Findings With a Founder Effect.

Objective: The purpose of this study was to improve our understanding of severe serine biosynthesis defects through a comprehensive description of prenatal, and postnatal manifestations and the mutational spectrum in a new cohort of 12 unrelated Egyptian Families.

Methods: Detailed fetal ultrasound examination, postnatal assessment, and whole exome sequencing (WES) were performed in a cohort of 12 fetuses with suspected Neu-Laxova syndrome (NLS), the most severe expression of serine biosynthesis defects. Additionally, a comprehensive review of the literature was conducted by merging the data from all the molecularly-confirmed cases with ours to gain a better understanding of the clinical variability of NLS.

Results: Novel clinical manifestations including intrauterine convulsions, hemivertebrae, natal teeth, holoprosencephaly, and rhombencephalosynapsis were observed. Molecular analysis identified 7 and 2 likely disease-causing variants in the PSAT1 and PHGDH genes, respectively. Four of them were novel, including the c.734G>A missense variant in PSAT1, which has been proposed to be a founder variant among Egyptians.

Conclusion: The present cohort expands the spectrum of serine biosynthesis disorders. Moreover, it illuminates the role of prenatal exome sequencing in lethal conditions constituting the most severe end of already-known human diseases.