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Publication
Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by
mutations in PHGDH.
Authors Shaheen R, Rahbeeni Z, Alhashem A, Faqeih E, Zhao Q, Xiong Y, Almoisheer A,
Al-Qattan SM, Almadani HA, Al-Onazi N, Al-Baqawi BS, Saleh MA, Alkuraya FS
Submitted By Submitted Externally on 7/24/2015
Status Published
Journal American journal of human genetics
Year 2014
Date Published 6/5/2014
Volume : Pages 94 : 898 - 904
PubMed Reference 24836451
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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