Genetic and prenatal diagnosis of a Chinese pedigree with pathogenic TOE1 variants causing pontocerebellar hypoplasia type 7.

Objective: Biallelic pathogenic variants in TOE1 cause pontocerebellar hypoplasia type 7 (PCH7), a rare neurological condition characterized by psychomotor retardation, spastic paraplegia, seizures, gonadal abnormalities and brain anomalies. Currently, only 14 postnatally diagnosed PCH7 patients have been described. However, the prenatal clinical profile of PCH7 has not yet been reported.Method: Whole-exome sequencing (WES) was performed to screen for causal variants.Results: We report the pedigree of a Chinese woman with two eventful pregnancies with fetuses that showed brain anomalies, including microcephaly, cerebral anomalies, enlarged ventricles, corpus callosum thinning, abnormal lateral fissure, underdeveloped insula and pons and brainstem hypoplasia. Interestingly, corpus callosum thinning was observed in fetus 1 but not in fetus 2. An abnormal lateral fissure and an underdeveloped insula were shown in fetus 2 but not fetus 1. Biallelic variants c.716T > C (p.Phe239Ser) and c.955C > T (p.His319Tyr) in TOE1 were identified in both fetuses.Conclusion: We first describe the prenatal features of a Chinese pedigree with PCH7 caused by biallelic pathogenic variants in TOE1, with phenotypic variability observed even within the same family. Novel phenotypes, an abnormal lateral fissure and an underdeveloped insula were observed in the fetus in our study. These findings will enrich our knowledge of the clinical characteristics, management and genetic counseling of PCH7.

Novel TARS2 variant identified in a Chinese patient with mitochondrial encephalomyopathy and a systematic review.

Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, delayed psychomotor development, epilepsy, and brain anomalies. Currently, eight COXPD21 patients have been reported in the literature, and 11 pathogenic variants in TARS2 have been identified. Here, we report a 2-year-6-month-old Chinese female who presented with severe dystonia, developmental regression, absent speech, and intractable epilepsy. Laboratory examination showed persistently increased serum lactate. Brain MRI showed that the head of the caudate and partial lenticular nucleus were bilateral symmetrical T2-weighted imaging (T2WI) hyperintense and the corpus callosum was very thin. The clinical characteristics pointed to a ME. Trio-based whole-exome sequencing (WES) was employed to detect the causative variants. WES revealed novel compound heterozygous variants, c.470G>C (p.Thr157Arg) and c.2051C>T (p.Arg684Gln), in TARS2 in our patient that were inherited from the mother and father, respectively. Next, we systematically reviewed the available clinical features of COXPD21 patients and noticed that the reduced fetal movement observed in our patient may be a novel phenotype of COXPD21. These findings expand the mutation spectrum of TARS2 and provide insights into the genotype-phenotype relationship in COXPD21 as well as a foundation for its genetic counseling, diagnosis and treatment.

[Genetic and clinical analysis of a novel GLB1 gene variant in a Chinese patient with GM1-gangliosidosis].

OBJECTIVE: To explore the genotype-phenotype correlation of a case with GM1-gangliosidosis caused by compound heterogenic variants in GLB1. METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Trio-based whole-exome sequencing (WES) was performed for the family and suspected mutation was verified by Sanger sequencing. RESULTS: The proband, a 2-year-3-month old Chinese girl, presented with psychomotor deterioration, absent speech, intellectual disabilities and behavior problem. Trio-based WES has identified compound heterozygosity for 2 variants in the GLB1 gene: NM_000404.2:c.1343A>T, p.Asp448Val and c.1064A>C, p.Gln355Pro (GRCh37/hg19),which was inherited from the mother and father, respectively. Homozygous or compound heterozygous pathogenic variants in GLB1, encoding ß-galactosidase, are responsible for GM1-gangliosidosis,an autosomal recessive lysosomal storage disorder characterized by variable degrees of neurodegeneration and skeletal abnormalities. The p.Asp448Val variant has been classified as pathogenic for GM1 gangliosidosis in medical literatures for the reason that functional studies demonstrated that expression of the p.Asp448Val variant in COS-1 cells resulted in no detectable ß-galactosidase activity compared to wild type GLB1. The p.Gln355Pro variant has not been reported in literatures or database. The variant is highly conserved residue (PM1), and was not found in either the Genome Aggregation Database or the 1000 Genomes Project (PM2) and was predicted to have a deleterious effect on the gene product by multiple in silico prediction tools (PP3). Next, the ß-galactosidase activity of the patient's peripheral blood leukocytes was determined by fluorescent method. The result was 0.0 nmol/mg. It showed that the p.Gln355Pro variant also resulted in loss of ß-galactosidase activity, thus the variant was classified into clinical pathogenic variant. CONCLUSION: Our study expands the mutational spectrum of the GLB1 gene and provides genetic counseling for the family.

[Genetic and clinical analysis of KIF2A gene variant in a Chinese patient with complex cortical dysplasia and other brain malformations].

OBJECTIVE: To explore the genetic basis for a child featuring complex cortical dysplasia and other brain malformations (CDCBM3). METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out for the family trio. Suspected variant was verified by Sanger sequencing. RESULTS: The proband, a 1-year-and-2-month old Chinese boy, had presented with motor developmental delay, lissencephaly, severe cognitive impairments, absent speech and congenital laryngomalacia. WES revealed that he has harbored a heterozygous missense variant of the KIF2A gene, namely NM_001098511.2: c.952G>A, p.Gly318Arg (GRCh37/hg19). The highly conserved residue is located around the ATP nucleotide-binding pocket in the kinesin motor domain (PM1). The variant was not found in the Genome Aggregation Database and the 1000 Genomes Project (PM2), and was predicted to be deleterious on the gene product by multiple in silico prediction tools (PP3). This variant was unreported previously and was de novo in origin (PS2). Based on the ACMG guidelines, it was categorized as likely pathogenic (PS2+PM1+PM2+PP3). Furthermore, the congenital laryngomalacia found in our patient was absent in previously reported CDCBM3 cases. CONCLUSION: The novel variant of the KIF2A gene probably underlay the disorders in the proband. Above finding has expanded the phenotypic and mutational spectrum of CDCBM3.

[Analysis of OCRL gene variant in a Chinese pedigree affected with Lowe syndrome].

OBJECTIVE: To explore the genotype-phenotype correlation of a Chinese pedigree affected with Lowe syndrome. METHODS: Whole exome sequencing (WES) and Sanger sequencing were carried out for the proband and members of his pedigree. RESULTS: The proband, a 3-year-and-5-month-old male, presented with multiple anomalies including congenital cataract, glaucoma, brain dysplasia, renal dysfunction and cognitive impairment. WES revealed that he has harbored a novel hemizygous missense variant of the OCRL gene, namely NM_000276.3: c.1255T>C (p.Trp419Arg) (GRCh37/hg19), which was derived from his unaffected mother. The same variant was not found in his elder brother who was healthy. The variant was predicted to be pathogenic according to ACMG/AMP guideline. Compared with previously reported cases of Lowe syndrome, our patient has displayed rare features including corpus callosum dysplasia, reduction of white matter, cerebral hypoplasia, laryngomalacia, sebaceous cyst, recurrent eczema, cryptorchidism, hypoglycemia and irritability. CONCLUSION: Above finding has expanded the mutational spectrum of the OCRL gene, enriched clinical features of Lowe syndrome, and enabled genetic counseling for this pedigree.

Updated incidence rates and risk factors of esophageal cancer in Nan'ao Island, a coastal high-risk area in southern China.

Esophageal cancer (EC) is one of the most common cancers in China. The purpose of this study was to investigate the updated incidence rates and risk factors of EC in Nan'ao Island, where the EC incidence rate was chronically the highest in southern China. To calculate the annual incidence rate, data on 338 EC cases from Nan'ao Cancer Registry system diagnosed during 2005-2011 were collected. A case-control study was conducted to explore the EC risk factors. One hundred twenty-five alive EC patients diagnosed during 2005-2011 and 250 controls were enrolled into the case-control study. A pre-test questionnaire on demography, dietary factors, drinking water treatment, and behavioral factors was applied to collect information of all participants. The average EC incidence rates during 2005-2011 were 66.09/105, 94.62/105, 36.83/105 for both genders, males and females, respectively, in Nan'ao Island. The EC incidence rate in males was 2.40- to 4.55-fold higher than that in females in the period from 2006 to 2011 (P < 0.05). Considering the onset age, males tend to be much younger than females and reached peak incidence rate at a younger age (P < 0.05). Drinking water treatment by filter (odds ratio [OR] = 0.28, 95% confidence interval [95% CI] = 0.13-0.58) and fruit consumption (OR = 0.55, 95% CI = 0.32-0.94) reduced the risk for EC. On the contrary, the pickled vegetables consumption (OR = 2.64, 95% CI = 1.46-4.76) and liquor drinking (OR = 2.32, 95% CI = 1.21-4.44) increased the risk for EC. These results may be of importance for future research on EC etiology and prevention strategies.