Case Report: Aarskog-scott syndrome caused by FGD1 gene variation: A family study.

Aarskog-Scott syndrome is a rare genetic disorder characterized by short stature, abnormal facial features, and digital and genital deformities. FGD1 gene variation is the known cause of this disorder. This paper described a Chinese family study of Aarskog-Scott syndrome in which the main patients were two brothers. Then, the relationship between genotype and phenotype in Aarskog-Scott syndrome was investigated preliminarily. A new FGD1 gene variant was revealed in this study, providing insights into the link between phenotype and genotype variations in Aarskog-Scott syndrome as well as a foundation for its diagnosis and treatment.

In Situ Growth of CoS2/ZnS Nanoparticles on Graphene Sheets as an Ultralong Cycling Stability Anode for Potassium Ion Storage.

Metal sulfides are promising anodes for potassium-ion batteries (PIBs) due to their high theoretical capacity and abundant active sites; however, their intrinsic low conductivity and poor cycling stability hampered their practical applications. Given this, the rational design of hybrid structures with high stability and fast charge transfer is a critical approach. Herein, CoS2/ZnS@rGO hybrid nanocomposites were demonstrated with stable cubic phases. The synergistic effect of the obtained bimetallic sulfide nanoparticles and highly conductive 2D rGO nanosheets facilitated excellent long-term cyclability for potassium ion storage. Such hybrid nanocomposites delivered remarkable ultrastable cycling performances in PIBs of 159, 106, and 80 mA h g-1 at 1, 1.5, and 2 A g-1 after 1800, 2100, and 3000 cycles, respectively. Moreover, the full-cell configuration with a perylene tetracarboxylic dianhydride organic cathode (CoS2/ZnS@rGO∥PTCDA) exhibited a better electrochemical performance. Besides, when the CoS2/ZnS@rGO nanocomposites were applied as an anode for sodium-ion batteries, the electrode demonstrated a reversible charge capacity of 259 mA h g-1 after 600 cycles at 2 A g-1. In situ X-ray diffraction and ex situ high-resolution transmission electron microscopy characterizations further confirmed the conversion reactions of CoS2/ZnS during insertion/desertion processes. Our synthesis strategy is also a general route to other bimetallic sulfide hybrid nanocomposites. This strategy opens up a new roadmap for exploring hybrid nanocomposites with feasible phase engineering for achieving excellent electrochemical performances in energy storage applications.

Clinical and molecular spectrum of CHOPS syndrome.

CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4. Previously, we reported three individuals whose primary phenotype included cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature. This syndrome overlaps phenotypically with Cornelia de Lange syndrome, but presents distinct differences including facial features, pulmonary involvement, and obesity. Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals. All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes. All 11 individuals had short stature and obesity. Congenital heart disease and pulmonary involvement were common, and those were seen in about 70% of individuals with CHOPS syndrome. Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density. Our observation indicates that obesity, pulmonary involvement, skeletal findings are the most notable features distinguishing CHOPS syndrome from Cornelia de Lange syndrome. In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing. These phenotypic findings establish CHOPS syndrome as a distinct, clinically recognizable disorder. Additionally, we report three novel missense mutations causative for CHOPS syndrome that lie within the highly conserved, 14 amino acid sequence of the ALF homology domain of the AFF4 gene, emphasizing the critical functional role of this region in human development.

[Molecular diagnosis of children with unexplained intellectual disability/ developmental delay by array-CGH].

OBJECTIVE: To analyze the potential pathogenic genomic imbalance in children with unexplained intellectual disability (ID) and/or developmental delay (DD) and its association with phenotypes, and to investigate the value of array-based comparative genomic hybridization (array-CGH) in clinical molecular genetic diagnosis. METHODS: The whole genome of 16 children with ID/DD was scanned by the array-CGH for detection of genomic copy number variations (CNVs), and the revealed genomic imbalance was confirmed by multiplex ligation-dependent probe amplification. RESULTS: G-band karyotyping of peripheral blood cells showed no abnormalities in the 16 children. The results of the array-CGH revealed that 6 (38%) of the 16 patients had genomic CNVs, and 3 cases of CNVs were normal polymorphic changes; 1 CNV was a microdeletion of 4p16.3, which was the critical region for Wolf-Hirschhorn syndrome, and 1 CNV was a microdeletion of 7q11.23, which was the critical region for Williams-Beuren syndrome. Moreover, a CNV was identified with two duplications at 2q22.2 and 15q21.3 in a boy, which proved to have a clinical significance due to its association with ID, brain DD, unusual facies, cryptorchidism, irregular dentition, etc. CONCLUSIONS: Array-CGH allows for the etiological diagnosis in some of the children with unexplained ID/DD. As a high-throughput and rapid tool, it has a great clinical significance in the etiological diagnosis of ID/DD.

[Analysis of clinical features, metabolic profiling and gene mutations of patients with ornithine transcarbamylase deficiency].

OBJECTIVE: To analyze the clinical features, metabolic profiling and gene mutations of patients with ornithine transcarbamylase deficiency (OTCD) and explore the molecular pathogenesis of OTCD in order to provide a solution for molecular diagnostics and genetic counseling. METHODS: Clinical data of 3 neonates were analyzed. The amino acids level in blood was analyzed with mass spectrum technology. PCR was used to amplify all the 10 exons of OTC gene. The PCR products were directly sequenced to detect the mutations. RESULTS: All of the 3 cases had neonatal onset and showed poor reaction, feeding difficulty, convulsion and neonatal infection. Citrulline levels were significantly decreased. Case 1 had a missense mutation of Y183C. Case 2 showed a missense mutation of V339G in exon 10. And a missense mutations of W332S in exon 9 was detected in case 3. CONCLUSION: Analysis of OTC gene sequences can be used for the diagnosis of OTCD and screening of asymptomatic carriers. Mutation analysis is important for prenatal diagnosis of individuals with a positive family history and genetic counseling. The V339G and W332S mutations have been discovered for the first time. Patients with such mutations may have onset of the disease during neonatal period.

Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy.

Duchenne/Becker muscular dystrophies are the most frequent inherited neuromuscular diseases caused by mutations of the dystrophin gene. However, approximately 30% of patients with the disease do not receive a molecular diagnosis because of the complex mutational spectrum and the large size of the gene. The introduction and use of next-generation sequencing have advanced clinical genetic research and might be a suitable method for the detection of various types of mutations in the dystrophin gene. To identify the mutational spectrum using a single platform, whole dystrophin gene sequencing was performed using next-generation sequencing. The entire dystrophin gene, including all exons, introns and promoter regions, was target enriched using a DMD whole gene enrichment kit. The enrichment libraries were sequenced on an Illumina HiSeq 2000 sequencer using paired read 100 bp sequencing. We studied 26 patients: 21 had known large deletion/duplications and 5 did not have detectable large deletion/duplications by multiplex ligation-dependent probe amplification technology (MLPA). We applied whole dystrophin gene analysis by next-generation sequencing to the five patients who did not have detectable large deletion/duplications and to five randomly chosen patients from the 21 who did have large deletion/duplications. The sequencing data covered almost 100% of the exonic region of the dystrophin gene by ≥10 reads with a mean read depth of 147. Five small mutations were identified in the first five patients, of which four variants were unreported in the dmd.nl database. The deleted or duplicated exons and the breakpoints in the five large deletion/duplication patients were precisely identified. Whole dystrophin gene sequencing by next-generation sequencing may be a useful tool for the genetic diagnosis of Duchenne and Becker muscular dystrophies.

Two homozygous nonsense mutations of GNPTAB gene in two Chinese families with mucolipidosis II alpha/beta using targeted next-generation sequencing.

Mucolipidosis II alpha/beta (ML II alpha/beta; I-cell disease) is a rare, inherited, metabolic disease and has often been clinically misdiagnosed. ML II alpha/beta results from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), which causes the lysosomal enzymes to accumulate in plasma. We identified two new Chinese patients with ML II alpha/beta by lysosomal enzyme assay. Using targeted next-generation sequencing genetic analysis, we located two homozygous nonsense mutations in the GNPTAB gene, c.1071G>A (p.W357X) and c.1090C>T (p.R364X). These results were confirmed by Sanger sequencing. To our knowledge, the c.1071G>A mutation has not been previously reported. Our findings add to the number of reported cases of this rare illness and to the GNPTAB pathogenic mutation database. This work also demonstrates the application of lysosomal enzyme assay and targeted next-generation sequencing for the genetic screening analysis and diagnosis of ML II alpha/beta.

The SEPS1 G-105A polymorphism is associated with risk of spontaneous preterm birth in a Chinese population.

Inflammation plays an important role in the etiology and pathophysiology of spontaneous preterm birth (SPTB), and selenoprotein S (SEPS1) is involved in regulating the inflammatory response. Recently the G-105A promoter polymorphism in SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined whether this functional polymorphism was related to the risk of SPTB in a Chinese population. We also examined the impact of premature rupture of membranes (PROM) on susceptibility to SPTB. The SEPS1 G-105A polymorphism was genotyped in 569 preterm singleton neonates and 673 term neonates by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. χ (2) tests and logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that, compared with the GG genotype, -105A positive genotypes (GA + AA genotypes) were associated with significantly increased susceptibility to SPTB (adjusted OR, 1.87; 95% CI, 1.36-2.57; P<0.001). The -105A positive genotypes were also significantly associated with increased susceptibility to SPTB, both in the patients with PROM (adjusted OR, 2.65; 95% CI, 1.73-4.03; P<0.001) and in those without PROM (adjusted OR, 1.56; 95% CI, 1.09-2.24; P = 0.015). The -105A positive genotypes were also significantly associated with increased susceptibility to SPTB between extremely preterm neonates and controls (adjusted OR, 4.46; 95% CI, 1.86-10.73; P = 0.002) and between moderately preterm neonates and controls (adjusted OR, 1.76; 95% CI, 1.25-2.47; P = 0.001). Our findings suggest that the SEPS1 G-105A polymorphism contributes to the risk of developing SPTB in a Chinese population.

Four novel GALC gene mutations in two Chinese patients with Krabbe disease.

Krabbe disease (OMIM #245200) is a rare autosomal recessive leukodystrophy caused by deficiency of galactocerebrosidase (GALC) activity. We identified four novel mutations of the GALC gene in two unrelated Chinese families with Krabbe disease: one insertion mutation, c.1836_1837insT, and one nonsense mutation, c.599C>A (p.S200X), in an infantile patient, and one deletion mutation, c.1911+1_1911+5delGTAAG, and one missense mutation, c.2041G>A, in an adult late-onset patient. This is the first identification of GALC mutations in the Chinese population.

Reference intervals for serum thyroid hormones in preterm hospitalized infants.

OBJECTIVE: In our study, the reference intervals of serum thyroid hormones were established in 247 hospitalized preterm infants from 28 to 36 weeks of gestation at 8-15 postnatal days. The thyroid hormones were serum triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), free thyroxine (FT4), and thyrotropin (TSH). METHODS: Electrochemiluminescence immunoassay was used to examine the thyroid hormone levels of serum samples from 247 preterm infants, who were grouped on sampling by gestational age. SPSS 16.0 was used to calculate the population-based reference intervals, in comparison to the manufacturer's suggested reference intervals. RESULTS: Kruskal-Wallis H tests could not determine the difference in TSH levels among groups, which allowed us to develop a single interval for the study population. ANOVA determined the differences in T3, FT3, T4, and FT4 levels among groups, which allowed us to define reference intervals for preterm infants according to their gestational age. CONCLUSION: Developed reference intervals are useful for clinical diagnosis; however, there is a lack of consensus. These values could be used to assess the thyroid status of preterm infants and provide a foundation for clinical therapy. The results emphasized the importance of establishing gestational age-based reference intervals for the clinical laboratory.

[Congenital central hypoventilation syndrome, report of three cases].

OBJECTIVE: To evaluate clinical characteristics and PHOX2B gene mutations in congenital central hypoventilation syndrome (CCHS) and to facilitate the early diagnosis and management of CCHS and reduce the misdiagnosis. METHOD: Clinical data of 3 infants with CCHS who had recurrent respiratory failure episodes and dependent on mechanical ventilation support in 3 from March 2008 to April 2012 were analyzed, and blood gas analysis was performed respectively in the awaken and sleeping status. Gene sequencing was used for detection of PHOX2B gene mutation. RESULT: All the three patients had adequate ventilation during awaken time, but they presented with abnormal frequency and shallow breathing associated with alveolar hypoventilation after falling asleep. Blood gas analysis showed hypercapnia and CO2 partial pressure was consistently over 60 mm Hg (1 mm Hg = 0.133 kPa) after falling asleep, which is in accordance with the clinical features of CCHS. The PHOX2B gene sequencing showed that 6 GCN repeats were inserted at exon3 of PHOX2B in case 1, at same position, 5 GCN repeats were inserted in case 2 and 3. CONCLUSION: Normal ventilation in awaken status while shallow slow breathing accompanied with hypercapnia in sleep are the main clinical characteristics of CCHS, which requires mechanical ventilation. Acquired mutation in exon 3 of PHOX2B gene encoding repeated GCN sequence seems to be the molecular etiology of these three patients.

[Clinical and molecular genetic analysis for a patient with glycogen storage disease â a].

OBJECTIVE: To investigate the mutation of glucose-6-phosphatase gene (G6PC gene) in a patient with glycogen storage disease Ⅰa. METHODS: PCR was used to amplify all five exons of G6PC gene. The PCR products were directly sequenced to detect the mutations. RESULTS: A heterozygous 743G>A mutation was found in the patient and his mother, resulting in the substitution of glycine (G) by arginine (R) in codon 222(G222R) in the putative membrane-spanning domain in human G6Pase, but not in his father and his sister. CONCLUSIONS: G222R mutation in G6PC gene was first identified in a patient with glycogen storage disease Ⅰa in mainland China.

[Clinical application of proportional assist ventilation in very low birth weight infants with ventilator dependence].

OBJECTIVE: To study the effect of proportional assist ventilation (PAV) on physiology and respiratory mechanics in very low birth weight (VLBW) infants with ventilator dependence by comparison with conventional assist/control (A/C) ventilation. METHODS: Forty-six infants with ventilator dependence were randomly divided into two groups according to the ventilation model: PAV (n=23) and A/C (n=23). The gain of resistive and elastic unloading was set based on the runway method in the PAV group. Ventilation parameters were set based on the conventional method in the A/C group. Infants were observed for 30 minutes three times per day for three consecutive days. Arterial gas analysis results, transcutaneous saturation of oxygen (SPO2), heart rate, blood pressure (BP), respiratory rate (RR), mean airway pressure (MAP), peak inspiratory pressure (PIP), tide volume (VT), minute volume (MV) and oxygenation index (OI), were compared between the two groups. RESULTS: Compared with the A/C group, PaO2 and OI in the PAV group were significantly higher while PIP and MAP were significantly lower. There were no significant differences in FiO2, SPO2, pH, PaCO2, PEEP, VT, MV and RR between the two groups. Although mean arterial blood pressure and heart rate in the PAV group were not different from the A/C group, beat-to-beat variabilities in systolic and diastolic arterial blood pressure were significantly lower in the PAV group than in the A/C group. CONCLUSIONS: PAV may safely maintain gas exchange at lower airway pressures compared with A/C ventilation in VLBW infants. It can also improve oxygenation and infant-ventilator synchronization.

[Value of methylation-specific mutiplex ligation-dependent probe in the diagnosis of Prader-Willi syndrome].

OBJECTIVE: Prader-Willi syndrome (PWS) with different pathogenesis has different clinical manifestations, prognosis and genetic risks. Pathogenesis of the disease cannot be explained by conventional diagnostic method MS-PCR. This study employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for the diagnosis of PWS in order to explore the role of this method in the diagnosis and assessment of pathogenesis of PWS. METHODS: A system antithetical method was employed. Peripheral blood samples were collected from 30 children for MS-PCR. Of the 30 children, 16 were diagnosed with PWS by MS-PCR and the other 14 showed negative MS-PCR. MS-MLPA kit Me028 was used to detect DNA extracted from the 30 samples. RESULTS: The results showed by MS-MLPA and MS-PCR were identical. MS-MLPA demonstrated that 4 cases were maternal uniparental disomy and 12 cases were paternal dfeletion in 15q11-q13 region. CONCLUSIONS: MS-MLPA is a reliable method of genetic testing for PWS which can distinguish pathogenesis of PWS.

Novel chromosomal translocation t(11;9)(p15;p23) involving deletion and duplication of 9p in a girl associated with autism and mental retardation.

We describe a 5-year-old girl presented with autism and mental retardation features. Conventional karyotyping revealed a novel unidirectional translocation t(11;9)(p15;p23). HumanCytoSNP-12 Chip analysis identified a 13 Mb deletion from 9p24.3 to 9p23 and a 12.5Mb duplication from 9p23 to 9p21.2. The karyotype was described as 45,XX,psu dic(11; 9)(p15;p23), which was reported for the first time here. The deleted region, extending from 9p24.3 to 9p23, overlaps with the candidate region for monosomy 9p syndrome and contains a potential autism spectrum disorders (ASD) locus. The duplication region extending from 9p23 to 9p21.2 was previously identified as a critical region for the 9p duplication syndrome. These results suggested that the apparently balanced de novo translocations could produce cryptic deletions or duplications, and the precise mapping of the abnormal area may improve clinical management.

[Genetic analysis of a supernumerary derivative chromosome 15].

OBJECTIVE: To detect and analyze a supernumerary derivative chromosome 15 with combined cytogenetic and molecular techniques, and to discuss the correlation between genomic copy number variations (CNVs) and clinical phenotypes. METHODS: G-banded chromosome analysis and multiplex ligation-dependent probe amplification (MLPA) were carried out. The whole genome of the patient was also analyzed with array-comparative genome hybridization(array-CGH). RESULTS: G-banding analysis indicated that the patient has a karyotype of 47, XY, + mar, with the supernumerary chromsome derived from 15q11-13 region spanning 9.8 Mb from locus 20477397 to 30298155. CONCLUSION: CNVs of 15q11-13 are associated with mental retardation, language development delay and autistic disorder. Conventional cytogenetic analysis with array-CGH may provide a platform for accurate detection of chromosomal aberrations, which can faciliate the study of genome rearrangement underlying various diseases.

[Chromosome analysis in 92 children with congenital mental retardation].

OBJECTIVE: To explore the chromosome karyotypes in children with mental retardation. METHODS: The peripheral blood lymphocytes from 92 children with congenital mental retardation were cultured and analysed by the G-band technique. RESULTS: Of the 92 cases, 43 cases (47%) showed chromosome abnormalities. Autosomal abnormalities were found in 35 cases (38%) and sex chromosome abnormalities were found in 8 cases (9%). A novel abnormal karyotype 45, XX, psu dic (11;9) (p15;p24) was found in a child. CONCLUSIONS: Chromosome abnormalities may be important cytogenetic factors for congenital mental retardation. Cytogenetic chromosome karyotypic analysis appears to be an important method for genetic screening of congenital mental retardation.

MicroRNA expression profile in hyperoxia-exposed newborn mice during the development of bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm neonates; the underlying pathogenesis is not fully understood. MicroRNAs (length 21-25 nucleotides) are ribonucleic acid (RNA) molecules that have important functions in development, cellular differentiation, apoptosis, proliferation, and migration; very little is known regarding their role in developmental lung diseases. METHODS: We exposed neonatal mice to either room air or 60% oxygen, beginning at birth, and we used microRNA microarray and real-time polymerase chain reaction on lung samples. RESULTS: The hyperoxia-exposed mice developed a lung injury that mimicked human BPD. Fifty-one microRNAs shared similar profiles in the hyperoxia-exposed BPD lungs and the normal lungs, which indicates that those microRNAs might play a protective role during the septation process. In the BPD lungs, compared to the control lungs, 14 microRNAs were up-regulated, and 7 microRNAs were down-regulated, which indicates that these microRNAs might play an important role in the development of BPD. Some of the candidate microRNAs can regulate cell proliferation. CONCLUSIONS: To our knowledge, this study is the first to identify microRNAs associated with BPD development, which provides a clue for further investigation of their function in BPD development.