Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability

• Published in: American journal of medical genetics. Part A 2015-06, Vol.167A (6), p.1323-1329
• Main Authors: Mattos, Eduardo P., Silva, André Anjos da, Magalhães, José Antônio A, Leite, Júlio César L., Leistner-Segal, Sandra, Gus-Kessler, Rejane, Perez, Juliano Adams, Vedolin, Leonardo M., Torreblanca-Zanca, Albertina, Lapunzina, Pablo, Ruiz-Perez, Victor L., Sanseverino, Maria Teresa V.
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Base Sequence; Brain Diseases - diagnosis; Brain Diseases - genetics; Brain Diseases - pathology; Carbohydrate Metabolism, Inborn Errors - diagnosis; Carbohydrate Metabolism, Inborn Errors - genetics; Carbohydrate Metabolism, Inborn Errors - pathology; Codon, Nonsense; Consanguinity; Female; Fetal Growth Retardation - diagnosis; Fetal Growth Retardation - genetics; Fetal Growth Retardation - pathology; Fetus; Gene Expression; Genes, Lethal; Genetic Variation; Genotype; Homozygote; Humans; Ichthyosis - diagnosis; Ichthyosis - genetics; Ichthyosis - pathology; Infant, Newborn; Limb Deformities, Congenital - diagnosis; Limb Deformities, Congenital - genetics; Limb Deformities, Congenital - pathology; magnetic resonance imaging; Male; Microcephaly - diagnosis; Microcephaly - genetics; Microcephaly - pathology; Molecular Sequence Data; Neu-Laxova syndrome; Pedigree; Phenotype; phosphoglycerate dehydrogenase; Phosphoglycerate Dehydrogenase - deficiency; Phosphoglycerate Dehydrogenase - genetics; prenatal diagnosis; Psychomotor Disorders - diagnosis; Psychomotor Disorders - genetics; Psychomotor Disorders - pathology; Seizures - diagnosis; Seizures - genetics; Seizures - pathology; Sequence Analysis, DNA; serine metabolism; Severity of Illness Index; Ultrasonography, Prenatal
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.36930

In some cases Neu‐Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre‐ and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR‐amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first‐cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype‐phenotype correlation between the degree of PHGDH inactivation and disease severity. © 2015 Wiley Periodicals, Inc.