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Am J Hum Genet. 2014 Jun 5;94(6):898-904. doi: 10.1016/j.ajhg.2014.04.015. Epub 2014 May 15.

Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH.

Author information

1
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
2
Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
3
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
4
Department of Pediatrics, King Fahad Medical City, Riyadh 59046, Saudi Arabia.
5
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
6
Pediatric metabolic laboratory, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
7
Maternal Fetal Department, Women's Specialist Hospital, King Fahad Medical City, Riyadh 59046, Saudi Arabia.
8
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.

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.

PMID:
24836451
PMCID:
PMC4121479
DOI:
10.1016/j.ajhg.2014.04.015
[Indexed for MEDLINE]
Free PMC Article
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