Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability.
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.
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.
Eduardo P
EP
Mattos
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.
André Anjos da
AA
Silva
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.
José Antônio A
JA
Magalhães
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Júlio César L
JC
Leite
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Sandra
S
Leistner-Segal
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Rejane
R
Gus-Kessler
Radiology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Juliano Adams
JA
Perez
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.
Leonardo M
LM
Vedolin
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.
Albertina
A
Torreblanca-Zanca
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.
Pablo
P
Lapunzina
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.
Victor L
VL
Ruiz-Perez
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Maria Teresa V
MT
Sanseverino
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002239:Carbohydrate Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018389:Codon, Nonsense; D003241:Consanguinity; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005333:Fetus; D015870:Gene Expression; D005804:Genes, Lethal; D014644:Genetic Variation; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007057:Ichthyosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D050543:Phosphoglycerate Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D011596:Psychomotor Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D012640:Seizures / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D016216:Ultrasonography, Prenatal
D018389:Codon, Nonsense; D050543:Phosphoglycerate Dehydrogenase
Neu-Laxova syndrome; magnetic resonance imaging; phosphoglycerate dehydrogenase; prenatal diagnosis; serine metabolism