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Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability.
Am J Med Genet A. 2015 Jun; 167(6):1323-9.AJ

Abstract

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.

Authors+Show Affiliations

Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil. Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil. Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.Fetal Medicine Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil. Internal Medicine Department, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.Radiology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.Radiology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil. Internal Medicine Department, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.INGEMM, Instituto de Genética Médica Y Molecular, Hospital Universitario La Paz, Madrid, Spain. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.INGEMM, Instituto de Genética Médica Y Molecular, Hospital Universitario La Paz, Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25913727

Citation

Mattos, Eduardo P., et al. "Identification of a Premature Stop Codon Mutation in the PHGDH Gene in Severe Neu-Laxova Syndrome-evidence for Phenotypic Variability." American Journal of Medical Genetics. Part A, vol. 167, no. 6, 2015, pp. 1323-9.
Mattos EP, Silva AA, Magalhães JA, et al. Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability. Am J Med Genet A. 2015;167(6):1323-9.
Mattos, E. P., Silva, A. A., Magalhães, J. A., Leite, J. C., Leistner-Segal, S., Gus-Kessler, R., Perez, J. A., Vedolin, L. M., Torreblanca-Zanca, A., Lapunzina, P., Ruiz-Perez, V. L., & Sanseverino, M. T. (2015). Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability. American Journal of Medical Genetics. Part A, 167(6), 1323-9. https://doi.org/10.1002/ajmg.a.36930
Mattos EP, et al. Identification of a Premature Stop Codon Mutation in the PHGDH Gene in Severe Neu-Laxova Syndrome-evidence for Phenotypic Variability. Am J Med Genet A. 2015;167(6):1323-9. PubMed PMID: 25913727.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability. AU - Mattos,Eduardo P, AU - Silva,André Anjos da, AU - Magalhães,José Antônio A, AU - Leite,Júlio César L, AU - Leistner-Segal,Sandra, AU - Gus-Kessler,Rejane, AU - Perez,Juliano Adams, AU - Vedolin,Leonardo M, AU - Torreblanca-Zanca,Albertina, AU - Lapunzina,Pablo, AU - Ruiz-Perez,Victor L, AU - Sanseverino,Maria Teresa V, Y1 - 2015/04/25/ PY - 2014/09/30/received PY - 2014/11/21/accepted PY - 2015/4/28/entrez PY - 2015/4/29/pubmed PY - 2016/2/18/medline KW - Neu-Laxova syndrome KW - magnetic resonance imaging KW - phosphoglycerate dehydrogenase KW - prenatal diagnosis KW - serine metabolism SP - 1323 EP - 9 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 167 IS - 6 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/25913727/Identification_of_a_premature_stop_codon_mutation_in_the_PHGDH_gene_in_severe_Neu_Laxova_syndrome_evidence_for_phenotypic_variability_ L2 - https://doi.org/10.1002/ajmg.a.36930 DB - PRIME DP - Unbound Medicine ER -