Publications by authors named "Bai-lin Wu"

72 Publications

A recurrent mutation in TBPL2 causes diminished ovarian reserve and female infertility.

J Genet Genomics 2020 Nov 18. Epub 2020 Nov 18.

Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410083, China; Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410083, China; Clinical Research Center For Reproduction and Genetics In Hunan Province, Changsha, 410083, China. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2020.09.004DOI Listing
November 2020

Developing a one-step triplet-repeat primed PCR assay for diagnosing myotonic dystrophy.

J Genet Genomics 2018 10 8;45(10):549-552. Epub 2018 Sep 8.

Children's Hospital of Fudan University, Shanghai 201102, China; Institute of Biomedical Sciences and Department of Pathology, Shanghai Medical College of Fudan University, Shanghai 200032, China; Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2018.06.008DOI Listing
October 2018

Association analysis between HFM1 variations and idiopathic azoospermia or severe oligozoospermia in Chinese Men.

Sci China Life Sci 2017 03 24;60(3):315-318. Epub 2016 Nov 24.

Clinical College of PLA Affiliated Anhui Medical University, Hefei, 230031, China.

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http://dx.doi.org/10.1007/s11427-016-0274-9DOI Listing
March 2017

Rare Deleterious PARD3 Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation.

Hum Mutat 2017 04 15;38(4):378-389. Epub 2017 Feb 15.

Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.

Increasing evidence that mutation of planar cell polarity (PCP) genes contributes to human cranial neural tube defect (NTD) susceptibility prompted us to hypothesize that rare variants of genes in the core apical-basal polarity (ABP) pathway are risk factors for cranial NTDs. In this study, we screened for rare genomic variation of PARD3 in 138 cranial NTD cases and 274 controls. Overall, the rare deleterious variants of PARD3 were significantly associated with increased risk for cranial NTDs (11/138 vs.7/274, P < 0.05, OR = 3.3). These NTD-specific variants were significantly enriched in the aPKC-binding region (6/138 vs. 0/274, P < 0.01). The East Asian cohort in the ExAC database and another Chinese normal cohort further supported this association. Over-expression analysis in HEK293T and MDCK cells confirmed abnormal aPKC binding or interaction for two PARD3 variants (p.P913Q and p.D783G), resulting in defective tight junction formation via disrupted aPKC binding. Functional analysis in human neural progenitor cells and chick embryos revealed that PARD3 knockdown gave rise to abnormal cell polarity and compromised the polarization process of neuroepithelial tissue. Our studies suggest that rare deleterious variants of PARD3 in the aPKC-binding region contribute to human cranial NTDs, possibly by disrupting apical tight junction formation and subsequent polarization process of the neuroepithelium.
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http://dx.doi.org/10.1002/humu.23153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513730PMC
April 2017

Extracellular Cl(-) regulates human SO4 (2-)/anion exchanger SLC26A1 by altering pH sensitivity of anion transport.

Pflugers Arch 2016 08 29;468(8):1311-32. Epub 2016 Apr 29.

Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.

Genetic deficiency of the SLC26A1 anion exchanger in mice is known to be associated with hyposulfatemia and hyperoxaluria with nephrolithiasis, but many aspects of human SLC26A1 function remain to be explored. We report here the functional characterization of human SLC26A1, a 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid (DIDS)-sensitive, electroneutral sodium-independent anion exchanger transporting sulfate, oxalate, bicarbonate, thiosulfate, and (with divergent properties) chloride. Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs in its stimulation by alkaline pHo and inhibition by acidic pHo but not pHi and in its failure to transport glyoxylate. SLC26A1-mediated transport of sulfate and oxalate is highly dependent on allosteric activation by extracellular chloride or non-substrate anions. Extracellular chloride stimulates apparent V max of human SLC26A1-mediated sulfate uptake by conferring a 2-log decrease in sensitivity to inhibition by extracellular protons, without changing transporter affinity for extracellular sulfate. In contrast to SLC26A1-mediated sulfate transport, SLC26A1-associated chloride transport is activated by acid pHo, shows reduced sensitivity to DIDS, and exhibits cation dependence of its DIDS-insensitive component. Human SLC26A1 resembles SLC26 paralogs in its inhibition by phorbol ester activation of protein kinase C (PKC), which differs in its undiminished polypeptide abundance at or near the oocyte surface. Mutation of SLC26A1 residues corresponding to candidate anion binding site-associated residues in avian SLC26A5/prestin altered anion transport in patterns resembling those of prestin. However, rare SLC26A1 polymorphic variants from a patient with renal Fanconi Syndrome and from a patient with nephrolithiasis/calcinosis exhibited no loss-of-function phenotypes consistent with disease pathogenesis.
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http://dx.doi.org/10.1007/s00424-016-1823-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956541PMC
August 2016

Quantitative evaluation of left ventricular volume and function in middle-aged healthy chinese people with 3 Tesla MRI.

J Magn Reson Imaging 2016 11 26;44(5):1143-1150. Epub 2016 Mar 26.

Department of Medical Imaging, Second Hospital, Hebei Medical University, Hebei, China.

Purpose: To quantitatively investigate left ventricular volume and function in middle-aged healthy subjects.

Materials And Methods: Ninety healthy volunteers underwent cardiac 3 Tesla MRI. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), cardiac output (CO), myocardial mass (MM), and their normalized indices (EDVI, ESVI, SVI, CI, and MI, respectively) after corrected with the body surface area (BSA) were analyzed and compared at different ages.

Results: All subjects had successfully completed the 3-Tesla cardiac MR. Females had significantly smaller EDV (110.5 ± 9.2 versus 125.7 ± 8.3 mL), ESV (36.1 ± 3.5 versus 41.5 ± 3.8 mL), SV (74.3 ± 6.3 versus 84.2 ± 6.7 mL), CO (5.4 ± 0.8 versus 5.8 ± 0.9 l/min) and MM (73.0 ± 10.5 versus 94.8 ± 10.6 g) than males (P < 0.05). The EF had no significant (P = 0.47) difference between genders (67.3 ± 1.7 percent in females versus 66.9 ± 2.4 percent in males). After normalization with BSA, no significant (P > 0.05) difference was detected between the genders in EDVI (71.2 ± 4.3 versus 71.1 ± 4.2 mL/m , P = 0.882), ESVI (23.3 ± 1.9 versus 23.5 ± 1.9 mL/m , P = 0.733) and SVI (47.9 ± 2.9 versus 47.7 ± 3.7 mL/m , P = 0.698) except for CI and MI. Females had significantly (P < 0.05) greater CI (3.5 ± 0.4 versus 3.3 ± 0.4) but smaller MI (46.9 ± 5.3 versus 53.6 ± 7.6) than males. EDV, EDVI, ESV, ESVI, SV, and SVI significantly (P < 0.05) decreased with age increase. BSA was positively correlated with EDV, ESV, SV, MM, and CO. No significance (P > 0.05) was detected in other parameters.

Conclusion: The left ventricular volume and function differs in women compared with men in the middle-aged population, and these parameters have a tendency of decrease with ageing. J. Magn. Reson. Imaging 2016;44:1143-1150.
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http://dx.doi.org/10.1002/jmri.25243DOI Listing
November 2016

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism.

Sci China Life Sci 2015 Oct;58(10):958-67

Children's Hospital of Fudan University, Institutes of Biomedical Science, Shanghai Medical College of Fudan University, Shanghai, 200032, China.

Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.
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http://dx.doi.org/10.1007/s11427-015-4941-1DOI Listing
October 2015

Parenting stress and affective symptoms in parents of autistic children.

Sci China Life Sci 2015 Oct;58(10):1036-43

Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.

We examined parenting stress and mental health status in parents of autistic children and assessed factors associated with such stress. Participants were parents of 188 autistic children diagnosed with DSM-IV criteria and parents of 144 normally developing children. Parents of autistic children reported higher levels of stress, depression, and anxiety than parents of normally developing children. Mothers of autistic children had a higher risk of depression and anxiety than that did parents of normally developing children. Mothers compared to fathers of autistic children were more vulnerable to depression. Age, behavior problems of autistic children, and mothers' anxiety were significantly associated with parenting stress.
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http://dx.doi.org/10.1007/s11427-012-4293-zDOI Listing
October 2015

Congenital chloride-losing diarrhea in a Mexican child with the novel homozygous SLC26A3 mutation G393W.

Front Physiol 2015 23;6:179. Epub 2015 Jun 23.

Renal Division, Beth Israel Deaconess Medical Center Boston, MA, USA ; Harvard Digestive Diseases Center, Harvard Medical School Boston, MA, USA ; Department of Medicine, Harvard Medical School Boston, MA, USA.

Congenital chloride diarrhea is an autosomal recessive disease caused by mutations in the intestinal lumenal membrane Cl(-)/HCO(-) 3 exchanger, SLC26A3. We report here the novel SLC26A3 mutation G393W in a Mexican child, the first such report in a patient from Central America. SLC26A3 G393W expression in Xenopus oocytes exhibits a mild hypomorphic phenotype, with normal surface expression and moderately reduced anion transport function. However, expression of HA-SLC26A3 in HEK-293 cells reveals intracellular retention and greatly decreased steady-state levels of the mutant polypeptide, in contrast to peripheral membrane expression of the wildtype protein. Whereas wildtype HA-SLC26A3 is apically localized in polarized monolayers of filter-grown MDCK cells and Caco2 cells, mutant HA-SLC26A3 G393W exhibits decreased total polypeptide abundance, with reduced or absent surface expression and sparse punctate (or absent) intracellular distribution. The WT protein is similarly localized in LLC-PK1 cells, but the mutant fails to accumulate to detectable levels. We conclude that the chloride-losing diarrhea phenotype associated with homozygous expression of SLC26A3 G393W likely reflects lack of apical surface expression in enterocytes, secondary to combined abnormalities in polypeptide trafficking and stability. Future progress in development of general or target-specific folding chaperonins and correctors may hold promise for pharmacological rescue of this and similar genetic defects in membrane protein targeting.
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http://dx.doi.org/10.3389/fphys.2015.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477073PMC
July 2015

Autistic children exhibit decreased levels of essential Fatty acids in red blood cells.

Int J Mol Sci 2015 May 4;16(5):10061-76. Epub 2015 May 4.

Laboratory of Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p<0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n=20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism.
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http://dx.doi.org/10.3390/ijms160510061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463632PMC
May 2015

Genetic Evaluation of Copy Number Variations, Loss of Heterozygosity, and Single-Nucleotide Variant Levels in Human Embryonic Stem Cells With or Without Skewed X Chromosome Inactivation.

Stem Cells Dev 2015 Aug 26;24(15):1779-92. Epub 2015 May 26.

1 Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory for Reproduction and Genetics of Guangdong Higher Education Institutes, Third Affiliated Hospital of Guangzhou Medical University , Guangzhou, People's Republic of China .

Human embryonic stem cells (hESCs) exhibiting skewed X chromosome inactivation (XCI) have been reported. The copy number variations (CNVs), loss of heterozygosity (LOH), or single-nucleotide variant (SNV) events in those epigenetically distinct cells remain unknown, and whether such genetic abnormalities will influence the XCI status of hESCs is unclear. In this study, three hESCs with skewed XCI, three with random XCI, and two male hESC lines at different passages were analyzed for CNVs and LOH levels using a high-resolution genotyping microarray. Whole-exome sequencing was used to investigate the potentially damaging SNVs. On average, 17.6 CNVs and 5.3 cases of LOH were identified in the skewed hESCs, which were similar to the rates observed in random hESCs. Five recurrent CNV regions were uniquely identified in the skewed hESCs, but all of them were considered polymorphisms. With the exception of a nongenic CNV, no additional CNVs were detected on the X chromosome in the skewed hESCs. Although the XCI status in two hESC lines was observed to be changed from random to skewed, no significant CNV difference was identified before and after the XCI change. SNV analysis indicated that normal alleles are maintained for most genes within copy-neutral LOH regions. Three types of expression patterns were observed in heterozygous alleles, and the damaging SNVs in skewed hESCs favored the expression of the wild-type alleles. In conclusion, in the present study, we did not find genetic differences in the CNV and LOH levels between hESCs with and without skewed XCI. Wild-type allele expression in the presence of damaging SNVs on the X chromosome in skewed hESCs might alleviate adverse effects in those hESCs.
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http://dx.doi.org/10.1089/scd.2014.0463DOI Listing
August 2015

Somatic mutations in cerebral cortical malformations.

N Engl J Med 2014 Aug;371(8):733-43

From the Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute (S.S.J., A.-T.N.L., A.M.D., B.J.B., X.Z., R.S.H., J.N.P., A.R., S.S., B.K.M., T.W.Y., C.A.W.), and the Departments of Laboratory Medicine (J.W., Y.S., B.L.W.) and Neurology (M.S., A.P.), Boston Children's Hospital, the Departments of Pediatrics (S.S.J., A.-T.N.L., A.M.D., B.J.B., X.Z., R.S.H., J.N.P., A.R., S.S., B.K.M., T.W.Y., C.A.W.), Neurology (S.S.J., A.-T.N.L., A.M.D., B.J.B., X.Z., R.S.H., J.N.P., A.R., S.S., B.K.M., T.W.Y., C.A.W., M.S., A.P.), and Pathology (Y.S., B.L.W.), Harvard Medical School, the Department of Neurology, Beth Israel Deaconess Medical Center (B.S.C.), and the Department of Neurology, Massachusetts General Hospital (T.W.Y.) - all in Boston; the Department of Paediatrics, KK Women's and Children's Hospital, Singapore, Singapore (S.S.J.); the Department of Genome Sciences, University of Washington, Seattle (M.K., M.B., D.A.N., J.S.); the Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai (J.W., Y.S.); the Division of Neurology, Department of Pediatrics, Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey (M.T.); the Neurogenetics Unit, Montreal Neurological Hospital and Institute, Department of Neurology and Neurosurgery (D.A., E.A.) and Department of Human Genetics (E.A.), McGill University, Montreal; the Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels (B.D.); the Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy (E.P., R.G.); the Department of Medicine, University of Melbourne, Austin Health, Heidelberg (I.E.S., S.F.B.), Department of Paediatrics, Royal Children's Hospital, University of Melbourne, and the Florey Institute of Neuroscience and Mental Health, Melbourne (I.E.S.), and the Department of Neurology, Royal Children's Hospital, Murdoch Children'

Background: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.

Methods: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.

Results: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.

Conclusions: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
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http://dx.doi.org/10.1056/NEJMoa1314432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274952PMC
August 2014

Analysis of CGG repeats in FMR1 in Chinese women with idiopathic premature ovarian failure.

Reprod Biomed Online 2014 Sep 15;29(3):382-7. Epub 2014 May 15.

State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China. Electronic address:

Excessive triple CGG repeats in the FMR1 gene have been widely associated with premature ovarian failure. The number of AGG interruptions and length of uninterrupted CGG repeats have been correlated with repeat instability on transmission. In this study, FMR1 CGG repeats and AGG interruption status were determined by triplet-primed PCR in 117 premature ovarian failure patients and 82 matched controls. A possible relationship between CGG repeats or AGG interruption and serum FSH concentrations in patients and controls was evaluated. One patient had a premutation allele (73 repeats) (1/117), while no such mutations were observed in controls (0/82). Other patients and all controls had CGG repeats in the normal range. There was no significant difference in the incidence of intermediate mutations of CGG repeats between patients and controls and no relationship between CGG repeats with serum FSH concentrations. Interestingly, more individuals with premature ovarian failure carried no AGG interruptions than the controls (4.27% versus 1.83%) but statistical significance was not reached. This small case-control study failed to find associations between CGG repeat sizes or AGG interruptions in FMR1 and premature ovarian failure in Chinese women. Further study with large sample size is warranted.
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http://dx.doi.org/10.1016/j.rbmo.2014.05.004DOI Listing
September 2014

Copy number variation plays an important role in clinical epilepsy.

Ann Neurol 2014 Jun 13;75(6):943-58. Epub 2014 Jun 13.

Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology and Neurogenetics Program, Department of Neurology, Boston Children's Hospital, and Harvard Medical School, Boston, MA.

Objective: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.

Methods: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA.

Results: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy.

Interpretation: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.
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http://dx.doi.org/10.1002/ana.24178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487364PMC
June 2014

Mutations in HFM1 in recessive primary ovarian insufficiency.

N Engl J Med 2014 Mar;370(10):972-4

Boston Children's Hospital, Boston, MA.

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http://dx.doi.org/10.1056/NEJMc1310150DOI Listing
March 2014

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

Hum Mol Genet 2014 May 30;23(10):2752-68. Epub 2013 Dec 30.

The Centre for Applied Genomics.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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http://dx.doi.org/10.1093/hmg/ddt669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990173PMC
May 2014

SOX12 and NRSN2 are candidate genes for 20p13 subtelomeric deletions associated with developmental delay.

Am J Med Genet B Neuropsychiatr Genet 2013 Dec 6;162B(8):832-40. Epub 2013 Sep 6.

Institutes of Biomedical Sciences, Children's Hospital and MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China; Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts.

20p13 telomeric/subtelomeric deletions are clinically significant but are currently under-investigated. So far only five molecularly delineated cases have been reported in literature and no candidate genes have been sufficiently implicated. Here, we present six new deletion cases identified by chromosomal microarray analysis (CMA). We also review 32 cases combined from literature and databases. We found that most 20p13 deletion patients exhibit significant developmental delay. Dysmorphic features are common but a consistent pattern was not recognized. Reduced cognitive ability was frequent. Based on pathogenic deletions delineated in this study, we mapped the smallest overlapping region and identified two nervous system expressing genes (SOX12 and NRSN2) as candidate genes that may be involved in the developmental defects in 20p13 microdeletion.
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http://dx.doi.org/10.1002/ajmg.b.32187DOI Listing
December 2013

Reply to Dr. Jeffrey Brent.

Authors:
Bai-Lin Wu Bo Song

Neurotoxicology 2013 Jul 24;37:220. Epub 2013 May 24.

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http://dx.doi.org/10.1016/j.neuro.2013.05.013DOI Listing
July 2013

Density matters: comparison of array platforms for detection of copy-number variation and copy-neutral abnormalities.

Genet Med 2013 Sep 4;15(9):706-12. Epub 2013 Apr 4.

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

Purpose: A combination of oligonucleotide and single-nucleotide polymorphism probes on the same array platform can detect copy-number abnormalities and copy-neutral aberrations such as uniparental disomy and long stretches of homozygosity. The single-nucleotide polymorphism probe density in commercially available platforms varies widely, which may affect the detection of copy-neutral abnormalities.

Methods: We evaluated the ability of array platforms with low (Oxford Gene Technology CytoSure ISCA uniparental disomy), mid-range (Agilent custom array), and high (Affymetrix CytoScan HD) single-nucleotide polymorphism probe density to detect copy-number variation, mosaicism, uniparental isodisomy, and absence of heterozygosity in 50 clinical samples.

Results: All platforms reliably detected copy-number variation, mosaicism, and uniparental isodisomy; however, absence-of-heterozygosity detection varied significantly. The low-density array called absence-of-heterozygosity regions not confirmed by the other platforms and also overestimated the length of true absence-of-heterozygosity regions. Furthermore, the low- and mid-density platforms failed to detect some small absence-of-heterozygosity regions that were identified by the high-density platform.

Conclusion: Variation in single-nucleotide polymorphism density can lead to major discrepancies in the detection of and confidence in copy-neutral abnormalities. Although suitable for uniparental disomy detection, copy-number plus single-nucleotide polymorphism arrays with 30,000 or fewer unique single-nucleotide polymorphism probes miscall absence-of-heterozygosity regions due to identity by descent.
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http://dx.doi.org/10.1038/gim.2013.36DOI Listing
September 2013

Molecular analysis of a deletion hotspot in the NRXN1 region reveals the involvement of short inverted repeats in deletion CNVs.

Am J Hum Genet 2013 Mar;92(3):375-86

Capital Institute of Pediatrics, Beijing, China.

NRXN1 microdeletions occur at a relatively high frequency and confer increased risk for neurodevelopmental and neurobehavioral abnormalities. The mechanism that makes NRXN1 a deletion hotspot is unknown. Here, we identified deletions of the NRXN1 region in affected cohorts, confirming a strong association with the autism spectrum and other neurodevelopmental disorders. Interestingly, deletions in both affected and control individuals were clustered in the 5' portion of NRXN1 and its immediate upstream region. To explore the mechanism of deletion, we mapped and analyzed the breakpoints of 32 deletions. At the deletion breakpoints, frequent microhomology (68.8%, 2-19 bp) suggested predominant mechanisms of DNA replication error and/or microhomology-mediated end-joining. Long terminal repeat (LTR) elements, unique non-B-DNA structures, and MEME-defined sequence motifs were significantly enriched, but Alu and LINE sequences were not. Importantly, small-size inverted repeats (minus self chains, minus sequence motifs, and partial complementary sequences) were significantly overrepresented in the vicinity of NRXN1 region deletion breakpoints, suggesting that, although they are not interrupted by the deletion process, such inverted repeats can predispose a region to genomic instability by mediating single-strand DNA looping via the annealing of partially reverse complementary strands and the promoting of DNA replication fork stalling and DNA replication error. Our observations highlight the potential importance of inverted repeats of variable sizes in generating a rearrangement hotspot in which individual breakpoints are not recurrent. Mechanisms that involve short inverted repeats in initiating deletion may also apply to other deletion hotspots in the human genome.
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http://dx.doi.org/10.1016/j.ajhg.2013.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591860PMC
March 2013

Reply to drs. John andrew tomenson and clive campbell.

Authors:
Bai-Lin Wu Bo Song

Neurotoxicology 2013 May 27;36:105. Epub 2013 Feb 27.

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http://dx.doi.org/10.1016/j.neuro.2013.02.011DOI Listing
May 2013

Detection of copy number variants reveals association of cilia genes with neural tube defects.

PLoS One 2013 17;8(1):e54492. Epub 2013 Jan 17.

Capital Institute of Pediatrics, Beijing, China.

Background: Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs.

Methods: The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined.

Results: Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways.

Conclusions: Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054492PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547935PMC
July 2013

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.

Am J Hum Genet 2013 Feb 17;92(2):210-20. Epub 2013 Jan 17.

Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.
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http://dx.doi.org/10.1016/j.ajhg.2012.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567268PMC
February 2013

Exome and whole-genome sequencing as clinical tests: a transformative practice in molecular diagnostics.

Clin Chem 2012 Nov 11;58(11):1507-9. Epub 2012 Oct 11.

Shanghai Children's Medical Center, Jiaotong University School of Medicine, Shanghai, China.

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http://dx.doi.org/10.1373/clinchem.2012.193128DOI Listing
November 2012

Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity.

Arch Gen Psychiatry 2012 Dec;69(12):1238-46

CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment. MAIN OUTCOME MEASURES Genomic copy number gains and losses. RESULTS We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.
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http://dx.doi.org/10.1001/archgenpsychiatry.2012.660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590016PMC
December 2012

[The effects of low pre-pregnant lead exposure level on maternal bone turnover during gestation and lactation in mice].

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2012 Jul;30(7):493-6

Department of Occupational and Environmental Health, Hebei Medical University, Shijiazhuang, Hebei, China.

Objective: To study the effects of low pre-pregnant lead exposure level on the mobilization of lead and calcium in maternal skeleton during gestation and lactation in mice.

Methods: Seventy Kunming female mice were randomly divided into the lead exposure or control groups, 36 mice were exposed to lead by drinking water (50 mg/L) and 36 mice were exposed to deionized water for 4 weeks. The levels of calcium and lead in blood and femurs were measured on the 1st, 7th and 14th days during gestation and on the 1st,10th and 21st days during lactation with atomic absorption spectrophotometry using a heated graphite atomizer or flame atomic absorption spectrophotometry.

Results: As compared with the pre-pregnant, at the end of lactation in exposure group the levels of calcium in blood and bones significantly decreased 18.5% and 17.75%, respectively, the levels of lead in blood significantly increased 65.22% and the levels of lead in bones significantly decreased 28.45% (P < 0.05). There was a significant negative correlation between the blood lead level and the bone lead level during gestation and lactation in exposure group (r = -0.904, P < 0.01). There were significant differences of lead and calcium levels during the gestation and lactation between exposure group and control group (P < 0.05).

Conclusion: The lead mobilization in maternal bone occurred during gestation and lactation in mice, which could be accelerated by the low pre-pregnant lead exposure.
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July 2012

Oligonucleotide microarrays for clinical diagnosis of copy number variation and zygosity status.

Curr Protoc Hum Genet 2012 Jul;Chapter 8:Unit8.12

Department of Laboratory Medicine, Division of Genetics, Children's Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.

Detection of submicroscopic genomic copy number variation is now considered the first-tier clinical test-in place of standard G-banded karyotyping-in the evaluation of children with unexplained developmental delay, intellectual disability, autism spectrum disorders, or congenital anomalies. Fluorescence in situ hybridization (FISH) was the first molecular method for detection of submicroscopic genomic copy number variants (CNVs), but microarray-based comparative genomic hybridization (array CGH) has a much higher diagnostic yield for these patients when compared to traditional cytogenetic methods such as karyotype and FISH. This unit focuses on oligonucleotide arrays, including updated information about detection of long contiguous stretches of homozygosity (LCSH) through inclusion of single-nucleotide polymorphism (SNP) probes. Most clinical laboratories now offer arrays with some level of probe coverage throughout the genome, and many are offering detection of LCSH. Updated guidelines for array design and result interpretation are reviewed.
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http://dx.doi.org/10.1002/0471142905.hg0812s74DOI Listing
July 2012

Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy.

Epilepsia 2012 Aug 12;53(8):e146-50. Epub 2012 Jun 12.

Department of Neurology, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants genome-wide and long-range polymerase chain reaction to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03538.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851296PMC
August 2012

Identification of novel rare mutations of DACT1 in human neural tube defects.

Hum Mutat 2012 Oct 19;33(10):1450-5. Epub 2012 Jun 19.

The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, P.R. China.

Neural tube defects (NTDs) constitute the second most frequent cause of human congenital abnormalities. Complex multigenetic causes have been suggested to contribute to NTDs. The planar cell polarity (PCP) pathway plays a critical role in neural tube closure in model organisms and in human. Knockout of Dact1 (Dapper, Frodo) leads to deregulated PCP signaling with defective neural tube in mice. Here, we report that five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. Our biochemical analyses revealed that among the five mutations, N356K and R45W show loss-of-function or reduced activities in inducing Dishevelled2 (DVL2) degradation and inhibiting jun-N-terminal kinase (JNK) phosphorylation, implicating mutated DACT1 as a risk factor for human NTDs. Our findings, together with early reports, suggest that rare mutations of the PCP-related genes may constitute a great contribution to human NTDs.
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http://dx.doi.org/10.1002/humu.22121DOI Listing
October 2012