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

ABSTRACT 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.