Neu-Laxova Syndrome, an Inborn Error of Serine Metabolism, is Caused by Mutations in PHGDH

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2014 May 20

PMID 24836451

Citations 38

Authors

Ranad Shaheen

Zuhair Rahbeeni

Amal Alhashem

Eissa Faqeih

Qi Zhao

Yong Xiong

Agaadir Almoisheer

Sarah M Al-Qattan

Halima A Almadani

Noufa Al-Onazi

Badi S Al-Baqawi

Mohammad Ali Saleh

Fowzan S Alkuraya

Affiliations

Soon will be listed here.

Abstract

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.

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