RNASEH2C c.194G>A is a Chinese-specific founder mutation in three unrelated patients with Aicardi-Goutières syndrome 3.

Biallelic pathogenic variants in RNASEH2C cause Aicardi-Goutières syndrome 3 (AGS3, MIM #610329), a rare early-onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese-specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3.

Injury during pregnancy and nervous system birth defects: Texas, 1999 to 2003.

BACKGROUND: Case reports and series have suggested an association between injury during pregnancy and several nervous system and nervous system-related adverse fetal/neonatal outcomes. This study's purpose is to further determine if there is an association between injury during pregnancy and nervous system birth defects in infancy. METHODS: Through a case-control study, the association between injury during pregnancy and nervous system birth defects was tested using the Texas Birth Defects Registry (1999-2003). Semiautomated probabilistic bias analysis was used to correct for systematic error from misclassification of injury during pregnancy. RESULTS: Of the 59,750 infants eligible for this study, 4144 (6.94%) were diagnosed with a nervous system birth defect and 315 (0.53%) of the infants' mothers were injured during pregnancy. Among these 315 women, 25 (7.94%) delivered an infant with a subsequent nervous system birth defect. The adjusted odds ratio for the association between injury during pregnancy and nervous system birth defects among all study infants was 1.00; 95% confidence interval, 0.63-1.56 and 2.44; 95% confidence interval, 1.08-5.53 among breech presentation infants. Probabilistic bias analysis supported these findings. CONCLUSION: No association between injury during pregnancy and nervous system birth defects was identified. Further exploration into the association among breech presentation infants is warranted.

Phenotypic spectrum of Fukutinopathy: most severe phenotype of Fukutinopathy.

Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, cobblestone lissencephaly, and eye anomalies. Among them, WWS is the most severe syndrome. Causative genes for FCMD (Fukutin), WWS (POMT1), and MEB (POMGnT1) have been identified. The vast majority of Japanese FCMD patients carry at least one copy of an ancestral founder insertion mutation. Patients homozygous for this insertion show a milder phenotype than do compound heterozygotes, carrying the insertion in combination with a missense or nonsense mutation on the other allele. No Japanese FCMD patients have been identified with nonfounder mutations on both alleles. A Turkish boy with characteristics of WWS was detected to have a homozygous nonsense mutation in exon 5 of Fukutin. This is the first case worldwide in which a Fukutin mutation has been found outside the Japanese population. Later, another Turkish boy with WWS phenotype was found to have a homozygous nonsense mutation in exon 4 of Fukutin. These two Turkish boys represent the most severe end of the phenotypic spectrum of Fukutin mutations. The Japanese FCMD patients carrying at least one copy of a founder mutation in the noncoding region may produce a lower level of mature Fukutin than normal and generate a relatively mild FCMD phenotype. The homozygous nonsense mutations within the coding region identified in Turkish patients are predicted to cause a total loss of fukutin activity and are likely to produce a more severe phenotype which closely resembles WWS.

Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.

BACKGROUND: Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population. In the present study, the authors were interested in finding new mutations in non-FC populations, assessing the activity of mutant proteins and refining genotype-phenotype correlations. METHODS: The authors screened KCC3 for mutations using direct sequencing in six non-FC HMSN/ACC families. They then assessed the functionality of the most common mutant protein using a flux assay in Xenopus laevis oocytes. RESULTS: The authors identified mutations in exon 22 of KCC3: a novel mutation (del + 2994-3003; E1015X) in one family, as well as a known mutation (3031C-->T; R1011X) found in five unrelated families and associated with two different haplotypes. The function of the cotransporter was abolished, although a limited amount of mutant proteins were correctly localized at the membrane. CONCLUSIONS: KCC3 mutations in exon 22 constitute a recurrent mutation site for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), regardless of ethnic origin, and are the most common cause of HMSN/ACC in the non-French Canadian (FC) families analyzed so far. Therefore, for genetic analysis, exon 22 screening should be prioritized in non-FC populations. Finally, the R1011X mutation leads to the abrogation of KCC3's function in Xenopus laevis oocytes, likely due to impaired transit of the cotransporter.

Racial differences in infant mortality attributable to birth defects in the United States, 1989-2002.

BACKGROUND: The objective is to study racial differences in infant mortality attributable to birth defects (IMBD) in the United States. METHODS: We analyzed 1989-1991 and 1995-2002 linked birth/death files for trends and racial differences in IMBD by selected categories of birth defects for infants of non-Hispanic white, non-Hispanic black, and Hispanic mothers. RESULTS: In 1989-2002, the IMBD rates declined. However, the decline in postneonatal mortality attributable to birth defects (PMBD) rate was significantly slower than that of overall postneonatal mortality. The adjusted rate ratio for non-Hispanic black and Hispanic versus non-Hispanic white for neonatal mortality attributable to birth defects (NMBD) remained unchanged from 1989-1991 through 2000-2002. For PMBD, it increased from 0.97 (95% confidence interval [CI], 0.90-1.13) in 1989-1991 to 1.12 (95% CI, 1.04-1.21) in 2001-2002 and from 1.08 (95% CI, 1.00-1.16) to 1.18 (95% CI, 1.10-1.27) for non-Hispanic black and Hispanic, respectively. Infant mortality due to cardiovascular and central nervous system defects were the main contributors to the increased racial disparities in PMBD rates. CONCLUSIONS: The disparity in PMBD between infants of non-Hispanic black and Hispanic mothers and infants of non-Hispanic white mothers increased significantly from 1989-1991 to 2000-2002. Further studies are needed to assess the extent to which delays in care or lack of access to care for infants with birth defects might be contributing to the disparity in IMBD.