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1.  Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange 
Journal of medical genetics  2008;46(9):626-634.
Cornelia de Lange Syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for ∼ 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (e.g. deletions and duplications) in the human genome, which result in gene copy number variations (CNV). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. We identified duplications on chromosomes 5 or X using genome wide array Comparative Genomic Hybridization (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and crainofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. Our results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new “reverse genomics” trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic etiology.
PMCID: PMC4302738  PMID: 19052029
Copy number changes; CNV; CdLS; NIPBL; cohesion complex
2.  [No title available] 
PMCID: PMC4294942  PMID: 21507892
3.  Recent advances in primary ciliary dyskinesia genetics 
Journal of Medical Genetics  2014;52(1):1-9.
Primary ciliary dyskinesia (PCD) is a rare genetically heterogeneous disorder caused by the abnormal structure and/or function of motile cilia. The PCD diagnosis is challenging and requires a well-described clinical phenotype combined with the identification of abnormalities in ciliary ultrastructure and/or beating pattern as well as the recognition of genetic cause of the disease. Regarding the pace of identification of PCD-related genes, a rapid acceleration during the last 2–3 years is notable. This is the result of new technologies, such as whole-exome sequencing, that have been recently applied in genetic research. To date, PCD-causative mutations in 29 genes are known and the number of causative genes is bound to rise. Even though the genetic causes of approximately one-third of PCD cases still remain to be found, the current knowledge can already be used to create new, accurate genetic tests for PCD that can accelerate the correct diagnosis and reduce the proportion of unexplained cases. This review aims to present the latest data on the relations between ciliary structure aberrations and their genetic basis.
PMCID: PMC4285891  PMID: 25351953
Cell biology; Diagnostics; Genetics; Molecular genetics
4.  A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signaling pathway and causes Lenz microphthalmia syndrome 
Journal of medical genetics  2014;51(3):185-196.
Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition.
Methods and results
Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells.
We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.
PMCID: PMC4278941  PMID: 24431331
5.  Autism traits in the RASopathies 
Journal of medical genetics  2013;51(1):10-20.
Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
PMCID: PMC4230531  PMID: 24101678
6.  Genome-wide association study of smoking behaviors among Bangladeshi adults 
Journal of medical genetics  2014;51(5):327-333.
The high prevalence of tobacco use in some developing nations, including Bangladesh, poses several public health challenges for these populations. Smoking behavior is determined by both genetic and environmental factors; however, the genetic determinants of smoking behavior have not been previously examined in a Bangladeshi or South Asian population. We performed a genome-wide association study (GWAS) of tobacco smoking behavior among a population-based sample of 5,354 (2,035 ever smokers and 3,319 never smokers) men and women in Bangladesh.
Genome-wide association analyses were conducted for smoking initiation (ever versus never smokers), smoking quantity (cigarettes per day), age of smoking initiation, and smoking cessation (former versus current smokers). Sex-stratified associations were performed for smoking initiation.
We observed associations for smoking initiation in the SLC39A11 region at 17q21.31 (rs2567519, P = 1.33 × 10−7) among males and in the SLCO3A1 region at 15q26 (rs12912184, P = 9.32 × 10−8) among females.
These findings suggest possible underlying mechanisms related to solute carrier transporter genes, which transport neurotransmitters, nutrients, heavy metals, and other substrates into cells, for smoking initiation in a South Asian population in a sex-specific pattern. Genetic markers could have potential translational implications for the prevention or treatment of tobacco use and addiction in South Asian populations and warrant further exploration.
PMCID: PMC4126189  PMID: 24665060
angladesh; environment and public health; genome-wide association study; smoking initiation; tobacco smoke
7.  De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder 
Journal of Medical Genetics  2014;51(11):737-747.
Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ∼70–80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints.
The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC).
IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD.
TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith–Magenis and Potocki–Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.
PMCID: PMC4215269  PMID: 25228304
Genetics; Molecular genetics; Chromosomal; Clinical genetics; Psychiatry
8.  Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing 
Journal of Medical Genetics  2014;51(11):724-736.
Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation.
We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases.
We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders.
With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.
PMCID: PMC4215287  PMID: 25167861
intellectual disability; mutation; high-throughput sequencing ; autism; causative
9.  Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size 
Journal of medical genetics  2013;50(10):666-673.
Individual differences in breast size are a conspicuous feature of variation in human females and have been associated with fecundity and advantage in selection of mates. To identify common variants that are associated with breast size, we conducted a large-scale genotyping association meta-analysis in 7,169 women of European descent across 3 independent sample collections with digital or screen film mammograms.
The samples consisted of the Swedish KARMA, LIBRO-1 and SASBAC studies genotyped on iCOGS, a custom illumina iSelect genotyping array comprising of 211,155 single nucleotide polymorphisms (SNPs) designed for replication and fine mapping of common and rare variants with relevance to breast, ovary and prostate cancer. Breast size of each subject was ascertained by measuring total breast area (mm2) on a mammogram.
We confirm genome-wide significant associations at 8p11.23 (rs10086016, P = 1.3 × 10−14) and report a new locus at 22q13 (rs5995871, P = 3.2 × 10−8). The latter region contains the MKL1 gene, which has been shown to impact endogenous estrogen-receptor α transcriptional activity and is recruited on estradiol-sensitive genes. We also replicated previous GWAS findings for breast size at four other loci.
A new locus at 22q13 may be associated with female breast size.
PMCID: PMC4159740  PMID: 23825393
Genome-wide association studies; population genetics; meta-analysis; breast size
10.  Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture 
Journal of medical genetics  2013;50(4):212-219.
Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population.
Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study.
In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10−8; OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis.
Our findings provide new insights into the genetic architecture underlying OF in East Asians.
PMCID: PMC4169276  PMID: 23349225
11.  CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles 
Journal of medical genetics  2014;51(5):309-318.
Greater than 200 CGG repeats in the 5′UTR of the FMR1 gene leads to epigenetic silencing and lack of the FMR1 protein, causing Fragile X Syndrome. Individuals carriers of a premutation (PM) allele with 55–200 CGG repeats are typically unmethylated and can present with clinical features defined as FMR1 associated conditions.
Blood samples from 17 male PM carriers were assessed clinically and molecularly by Southern Blot, Western Blot, PCR and QRT-PCR. Blood and brain tissue from additional 18 PM males were also similarly examined. Continuous outcomes were modeled using linear regression and binary outcomes were modeled using logistic regression.
Methylated alleles were detected in different fractions of blood cells in all PM cases (n= 17). CGG repeat numbers correlated with percent of methylation and mRNA levels and, especially in the upper PM range, with greater number of clinical involvements. Inter/intra- tissue somatic instability and differences in percent methylation were observed between blood and fibroblasts (n=4) and also observed between blood and different brain regions in three of the 18 premutation cases examined. CGG repeat lengths in lymphocytes remained unchanged over a period of time ranging from 2–6 years, three cases for whom multiple samples were available.
In addition to CGG size instability, individuals with a PM expanded alleles can exhibit methylation and display more clinical features likely due to RNA toxicity and/or FMR1 silencing. The observed association between CGG repeat length and percent of methylation with the severity of the clinical phenotypes underscores the potential value of methylation in affected PM to further understand penetrance, inform diagnosis and to expand treatment options.
PMCID: PMC4010431  PMID: 24591415
premutation; methylation; FMR1; somatic instability
12.  A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia 
Journal of Medical Genetics  2014;51(9):590-595.
Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume.
Methods and results
Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis.
This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy.
PMCID: PMC4145425  PMID: 25062847
Neurology; Clinical Genetics
13.  Correction 
Journal of Medical Genetics  2014;51(9):613.
PMCID: PMC4145464
14.  Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases 
Journal of medical genetics  2009;46(8):562-568.
Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snaillike configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD.
To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group.
Methods and results
We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases.
Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.
PMCID: PMC4144354  PMID: 19508970
15.  A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia 
Journal of medical genetics  2013;50(8):543-551.
We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia. Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C. elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels. We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia.
PMCID: PMC4133931  PMID: 23749989
chromosomal translocation; PTK2; FAK; THOC2; cerebellar hypoplasia
16.  Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18) 
Journal of medical genetics  2013;51(2):132-136.
Bardet-Biedl Syndrome (BBS) is a recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, post-axial polydactyly, behavioral dysfunction and hypogonadism. Seven of the 17 BBS gene products identified to date assemble together with the protein BBIP1/BBIP10 into the BBSome, a protein complex that ferries signaling receptors to and from cilia.
Methods and results
Exome sequencing performed on a sporadic BBS case revealed for the first time a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. This mutation is pathogenic since no BBIP1 protein could be detected in fibroblasts from the patient and BBIP1[Leu58*] is unable to associate with the BBSome subunit BBS4.
These findings identify BBIP1 as the eighteenth BBS gene (BBS18) and suggest that BBSome assembly may represent a unifying pathomechanism for BBS.
PMCID: PMC3966300  PMID: 24026985
Cilia; BBS; ciliopathy; exome sequencing; BBSome; BBIP1
17.  Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis 
Journal of medical genetics  2013;50(4):246-254.
Corneal intraepithelial dyskeratosis is an extremely rare condition. The classical form, affecting Native American Haliwa-Saponi tribe members, is called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present a new form of corneal intraepithelial dyskeratosis for which we identified the causative gene by using deep sequencing technology.
Methods and results
A seven member Caucasian French family with two corneal intraepithelial dyskeratosis affected individuals (6-year-old proband and his mother) was ascertained. The proband presented with bilateral complete corneal opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal dyskeratosis were associated with the phenotype. Histopathology studies of cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative PCR ruled out 4q35 duplication, classically described in HBID cases. Next generation sequencing with mean coverage of 50× using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variants and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with available databases were performed. A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This was a de novo mutation in the proband’s mother, following segregation in the family, and not found in 738 control DNA samples. NLRP1 expression was determined in adult corneal epithelium. The amino acid change was found to destabilise significantly the protein structure.
We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene. The NLRP1 gene product is implicated in inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 polymorphisms are associated with various diseases.
PMCID: PMC4115150  PMID: 23349227
18.  Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis type 3 
Journal of medical genetics  2011;48(5):343-352.
Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898).
To carry out a genotype–phenotype study of patients with FHL3.
A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database.
84 patients with FHL3 (median age 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=12). Their ethnic origin was Caucasian (n=57), Turkish (n=10), Asian (n=7), Hispanic (n=4), African (n=3) (not reported (n=3)). Thrombocytopenia was present in 94%, splenomegaly in 96%, fever in 89%. The central nervous system (CNS) was involved in 49/81 (60%) patients versus 36% in patients with FHL2 (p=0.001). A combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia was present in 71%. CD107a expression, NK activity and Munc 13-4 protein expression were absent or reduced in all but one of the evaluated patients. 54 different mutations were observed, including 15 new ones: 19 missense, 14 deletions or insertions, 12 nonsense, nine splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p<0.001), but older than comparable patients with FHL2 (p=0.001).
UNC13D mutations are scattered over the gene. Ethnic-specific mutations were not identified. CNS involvement is more common than in FHL2; in patients with FHL3 and disruptive mutations, age at diagnosis is significantly higher than in FHL2. The combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia appears to be the most easily and frequently recognised clinical pattern and their association with defective granule release assay may herald FHL3.
PMCID: PMC4115201  PMID: 21248318
19.  STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5 
Journal of medical genetics  2010;47(9):595-600.
Familial haemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with uncontrolled inflammation; the clinical course usually starts within the first years of life, and is usually fatal unless promptly treated and then cured with haematopoietic stem cell transplant. FHL is caused by genetic mutations resulting in defective cell cytotoxicity; three disease related genes have been identified to date: perforin, Munc13-4 and syntaxin-11. A fourth gene, STXBP2, has been identified very recently as responsible for a defect in Munc18-2 in FHL-5.
To describe the result of the screening of families with HLH and previously unassigned genetic defects.
Patients with HLH diagnosed according to current diagnostic criteria, and who lacked mutations in the PRF1, Munc13-4, and STX11 genes were sequenced for mutations in STXBP2. Functional study was performed when material was available.
Among the 28 families investigated, 4 (14%) with biallelic STXBP2 mutations were identified. They originated from Italy, England, Kuwait and Pakistan. The p.Pro477Leu resulting from c.1430C>T, and p.Arg405Gln resulting from the single c.1214G>A nucleotide change are known, while we contribute two novel mutations: p.Glu132Ala resulting from c.395A>C, and p.Gly541Ser, resulting from c.1621G>A. The detrimental effect of the p.Gly541Ser mutation was documented biochemically and functionally in NK and CD8 cells. Additional polymorphisms are also described.
These data expand current knowledge on the genetic heterogeneity of FHL and suggest that patients with FHL5 may have different results in degranulation assays under different conditions.
PMCID: PMC4115259  PMID: 20798128
20.  Transcobalamin II Receptor Polymorphisms Are Associated with Increased Risk for Neural Tube Defects 
Journal of medical genetics  2010;47(10):677-685.
Women who have low cobalamin (vitamin B12) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. We evaluated inherited variants in the TCblR gene as NTD risk factors.
Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings.
We found two tightly linked variants associated with NTDs in a recessive model: TCblR rs2336573 (G220R) (pcorr=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (pcorr =0. 0279). These variants were also associated with NTDs in a family-based test prior to multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R) (RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). We describe a copy number variant (CNV) distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms.
TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly one thousand controls, indicating this NTD risk factor may be of low frequency and high penetrance. Nine other variants are in perfect LD with the associated SNPs. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.
PMCID: PMC4112773  PMID: 20577008
neural tube defects; spina bifida; transcobalamin II receptor (TCblR); cobalamin; vitamin B12; copy number variant (CNV)
21.  Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders 
Journal of medical genetics  2008;46(4):242-248.
Segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or EEG abnormalities.
DNA samples from 1,445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1,441 individuals with Autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.
We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4–BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4–BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, ADHD, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4–BP5 covers ~1.5Mb (chr15:28.719–30.298Mb) and includes 6 reference genes and 1 miRNA gene, while the smaller duplications cover ~500 kb (chr15:28.902–29.404 Mb) and contain 3 reference genes and one miRNA gene. The BP4–BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG.
The phenotype of chromosome 15q13.2q13.3 BP4–BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying etiology of this syndrome.
PMCID: PMC4090085  PMID: 18805830
array CGH; autism; language delay; microdeletion/duplication; neuropsychiatric disorders
22.  Meta-Analysis of Genome-Wide Studies Identifies MEF2C SNPs Associated with Bone Mineral Density at Forearm 
Journal of medical genetics  2013;50(7):473-478.
Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown.
To identify genetic variants associated with forearm BMD and forearm fractures.
BMD at distal radius measured by dual-energy X-ray absorptiometry was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5,866 subjects of European descent and then selected variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-SNP test. We then tested the BMD-associated SNPs for association with forearm fracture in 2,023 cases and 3,740 controls.
We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (P<5×10−8) in meta-analysis (lead SNP, rs11951031[T] −0.20 standard deviations per allele, P=9.01×10−9). The gene-based association test suggested an association between MEF2C and forearm BMD (P=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: odds ratio = 1.14 [95% CI: 0.92–1.35], P = 0.14). Meta analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2.
These findings demonstrate that variants at MEF2C were associated with forearm BMD thereby implicating this gene in the determination of bone mineral density at forearm.
PMCID: PMC3769185  PMID: 23572186
Genome-wide association study; Osteoporosis; Bone mineral density; Forearm; Fracture; Meta-analysis; Gene-base; Conditional analysis
23.  Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations 
Journal of medical genetics  2013;50(6):383-392.
Nemaline myopathy—the most common non-dystrophic congenital myopathy—is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations.
Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 µM CK-2066260 on force production was assessed.
Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation—without affecting the cooperativity of activation—in patients to levels that exceed those observed in untreated control muscle.
Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.
PMCID: PMC3865762  PMID: 23572184
24.  A balanced translocation truncates Neurotrimin in a family with intracranial and thoracic aortic aneurysm 
Journal of medical genetics  2012;49(10):621-629.
Balanced chromosomal rearrangements occasionally have strong phenotypic effects, which may be useful in understanding pathobiology. However, conventional strategies for characterizing breakpoints are laborious and inaccurate. We present here a proband with a thoracic aortic aneurysm and a balanced translocation t(10;11)(q23.2;q24.2). Our purpose was to sequence the chromosomal breaks in this family to reveal a novel candidate gene for aneurysm.
Methods and results
Intracranial and thoracic aortic aneurysms appear to run in the family in an autosomal dominant manner: After exploring the family history, we observed that the proband’s two siblings both died from cerebral hemorrhage, and the proband’s parent and parent’s sibling died from aortic rupture. After application of a genome-wide paired-end DNA sequencing method for breakpoint mapping, we demonstrate that this translocation breaks intron 1 of a splicing isoform of Neurotrimin (NTM) at 11q25 in a previously implicated candidate region for intracranial (IAs) and aortic aneurysms (AAs) (OMIM 612161).
Our results demonstrate the feasibility of genome-wide paired-end sequencing for the characterization of balanced rearrangements and identification of candidate genes in patients with potentially disease-associated chromosome rearrangements. The family samples were gathered as a part of our recently launched National Registry of Reciprocal Balanced Translocations and Inversions in Finland (n=2575), and we believe that such a registry will be a powerful resource for the localization of chromosomal aberrations, which can bring insight into the etiology of related phenotypes.
PMCID: PMC4039200  PMID: 23054244
Molecular genetics; Cardiovascular Medicine; Chromosomal; Clinical Genetics; Genome-wide
25.  OPA1 increases the risk of normal but not high tension glaucoma 
Journal of medical genetics  2009;47(2):120-125.
Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterised by the selective loss of retinal ganglion cells (RGCs), pathological optic disc cupping and visual field defects. The OPA1 gene encodes for an inner mitochondrial membrane protein crucial for normal mitochondrial function and pathogenic mutations cause autosomal dominant optic atrophy (DOA) by specifically targeting RGCs. This raises the distinct possibility that more subtle genetic variations in OPA1 could alter the risk of developing glaucoma.
We studied 137 POAG patients, 67 patients with high tension glaucoma (HTG), 70 patients with normal tension glaucoma (NTG), and 75 controls from the North East of England. Three single nucleotide polymorphisms (SNPs) in intron 8 (IVS8+4c>t and IVS8+32t>c) and exon 4 (c.473A>G) of the OPA1 gene were genotyped in our study group. In addition, the entire OPA1 coding region was sequenced in 24 individuals with the CT/TT compound genotype using standard BigDye™ chemistries.
There was no difference in either allele or genotype frequency for the IVS8+32t>c SNP between patients and controls, but there was a significant association between the T allele at IVS8+4c>t and the risk of developing NTG (Odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.10-3.81, P = 0.004), but not HTG. Logistic regression analysis also confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR = 29.75, 95% CI = 3.83-231.21, P < 0.001).
The CT/TT compound genotype at IVS8+4 and IVS8+32 is a strong genetic risk determinant for NTG but not HTG.
PMCID: PMC4038487  PMID: 19581274
Dominant optic atrophy; glaucoma; haplogroup; mitochondria; optic nerve; OPA1

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