Publications by authors named "Alexandre Dionne-Laporte"

53 Publications

DOORS syndrome and a recurrent truncating ATP6V1B2 variant.

Genet Med 2021 01 2;23(1):149-154. Epub 2020 Sep 2.

Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada.

Purpose: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant.

Methods: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants.

Results: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found.

Conclusion: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.
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http://dx.doi.org/10.1038/s41436-020-00950-9DOI Listing
January 2021

Oligogenicity, C9orf72 expansion, and variant severity in ALS.

Neurogenetics 2020 07 8;21(3):227-242. Epub 2020 May 8.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

"Oligogenic inheritance" is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sclerosis (ALS). We sequenced ALS-associated genes in C9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly higher in C9orf72-negative ALS cases, suggesting sufficiency of C9orf72 expansion to cause ALS alone.
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http://dx.doi.org/10.1007/s10048-020-00612-7DOI Listing
July 2020

Machine learning analysis of exome trios to contrast the genomic architecture of autism and schizophrenia.

BMC Psychiatry 2020 02 28;20(1):92. Epub 2020 Feb 28.

Department of Human Genetics, McGill University, Montreal, QC, Canada.

Background: Machine learning (ML) algorithms and methods offer great tools to analyze large complex genomic datasets. Our goal was to compare the genomic architecture of schizophrenia (SCZ) and autism spectrum disorder (ASD) using ML.

Methods: In this paper, we used regularized gradient boosted machines to analyze whole-exome sequencing (WES) data from individuals SCZ and ASD in order to identify important distinguishing genetic features. We further demonstrated a method of gene clustering to highlight which subsets of genes identified by the ML algorithm are mutated concurrently in affected individuals and are central to each disease (i.e., ASD vs. SCZ "hub" genes).

Results: In summary, after correcting for population structure, we found that SCZ and ASD cases could be successfully separated based on genetic information, with 86-88% accuracy on the testing dataset. Through bioinformatic analysis, we explored if combinations of genes concurrently mutated in patients with the same condition ("hub" genes) belong to specific pathways. Several themes were found to be associated with ASD, including calcium ion transmembrane transport, immune system/inflammation, synapse organization, and retinoid metabolic process. Moreover, ion transmembrane transport, neurotransmitter transport, and microtubule/cytoskeleton processes were highlighted for SCZ.

Conclusions: Our manuscript introduces a novel comparative approach for studying the genetic architecture of genetically related diseases with complex inheritance and highlights genetic similarities and differences between ASD and SCZ.
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http://dx.doi.org/10.1186/s12888-020-02503-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049199PMC
February 2020

Mineral absorption is an enriched pathway in a brain region of restless legs syndrome patients with reduced MEIS1 expression.

PLoS One 2019 14;14(11):e0225186. Epub 2019 Nov 14.

McGill University, Montreal Neurological Institute, Montréal, QC, Canada.

Restless legs syndrome is a common complex disorder with different genetic and environmental risk factors. Here we used human cell lines to conduct an RNA-Seq study and observed how the gene showing the most significant association with RLS, MEIS1, acts as a regulator of the expression of many other genes. Some of the genes affected by its expression level are linked to pathways previously reported to be associated with RLS. We found that in cells where MEIS1 expression was either increased or prevented, mineral absorption is the principal dysregulated pathway. The mineral absorption pathway genes, HMOX1 and VDR are involved in iron metabolism and response to vitamin D, respectively. This shows a strong functional link to the known RLS pathways. We observed the same enrichment of the mineral absorption pathway in postmortem brain tissues of RLS patients showing a reduced expression of MEIS1. The expression of genes encoding metallothioneins (MTs) was observed to be dysregulated across the RNA-Seq datasets generated from both human cells and tissues. MTs are highly relevant to RLS as they bind intracellular metals, protect against oxidative stress and interact with ferritins which manage iron level in the central nervous system. Overall, our study suggests that in a subset of RLS patients, the contribution of MEIS1 appears to be associated to its downstream regulation of genes that are more directly involved in pathways that are relevant to RLS. While MTs have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's diseases, this is a first report to propose that they have a role in RLS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855629PMC
March 2020

Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia.

J Child Neurol 2020 02 16;35(2):106-110. Epub 2019 Oct 16.

Department of Pediatrics, Division of Pediatric Neurology, McGill University, Montreal, Quebec, Canada.

The term encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to : pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel heterozygous pathogenic missense variant (c.1310G>A) in in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.
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http://dx.doi.org/10.1177/0883073819878917DOI Listing
February 2020

De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.

Am J Hum Genet 2019 10;105(4):854-868

Montreal Neurological Institute, McGill University, H3A 2B4, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, H3A 2B4, Montreal, QC, Canada.

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs4]; c.2564_2567dupTGTT [p.Leu856Phefs5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).
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http://dx.doi.org/10.1016/j.ajhg.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817525PMC
October 2019

SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia.

J Hum Genet 2019 Nov 12;64(11):1145-1151. Epub 2019 Sep 12.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.
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http://dx.doi.org/10.1038/s10038-019-0669-2DOI Listing
November 2019

Genetic architecture and adaptations of Nunavik Inuit.

Proc Natl Acad Sci U S A 2019 08 22;116(32):16012-16017. Epub 2019 Jul 22.

Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada H3A 2B4;

The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit ∼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (, , , and ). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; = 4.6 × 10).
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http://dx.doi.org/10.1073/pnas.1810388116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689950PMC
August 2019

Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.

Clin Genet 2019 09 30;96(3):199-206. Epub 2019 May 30.

Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.

Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD-association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high-priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well-established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.
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http://dx.doi.org/10.1111/cge.13556DOI Listing
September 2019

Pathogenic variants in AIMP1 cause pontocerebellar hypoplasia.

Neurogenetics 2019 05 28;20(2):103-108. Epub 2019 Mar 28.

Departments of Pediatrics, Neurology & Neurosurgery, MUHC-Research Institute, McGill University, 1001 Blvd Décarie, Montreal, H4A 3J1, Canada.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex which catalyzes the ligation of amino acids to the correct tRNAs. Pathogenic variants in several aminoacyl-tRNA synthetases genes have been linked to various neurological disorders, including leukodystrophies and pontocerebellar hypoplasias (PCH). To date, loss-of-function variants in AIMP1 have been associated with hypomyelinating leukodystrophy-3 (MIM 260600). Here, we report a novel frameshift AIMP1 homozygous variant (c.160delA,p.Lys54Asnfs) in a child with pontocerebellar hypoplasia and simplified gyral pattern, a phenotype not been previously described with AIMP1 variants, thus expanding the phenotypic spectrum. AIMP1 should be included in diagnostic PCH gene panels.
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http://dx.doi.org/10.1007/s10048-019-00572-7DOI Listing
May 2019

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

Mov Disord 2019 04 20;34(4):526-535. Epub 2019 Feb 20.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.

Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.

Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.

Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469643PMC
April 2019

Screening of novel restless legs syndrome-associated genes in French-Canadian families.

Neurol Genet 2018 Dec 20;4(6):e296. Epub 2018 Dec 20.

Department of Human Genetics (F.A., Z.G.-O., G.A.R.), McGill University; Montreal Neurological Institute (F.A., D.S., A.D.-L., Z.G.-O., P.A.D., G.A.R.), McGill University; and Department of Neurology and Neurosurgery (Z.G.-O., P.A.D., G.A.R.), McGill University, Montréal, Quebec, Canada.

Objective: To examine whether any rare, protein-altering variants could be identified across 13 recently identified restless legs syndrome (RLS) loci in familial French-Canadian cases.

Methods: Whole-exome sequences from 7 large French-Canadian families (4-8 affected per family for a total of 38 cases) were examined for variants in any genes located within 1 Mb on either side of each locus.

Results: Among the 43 rare protein-altering variants identified, none segregated with RLS in the families.

Conclusions: Our study does not support a role for causative protein-altering variants in the genes that are located either in the previously or newly identified RLS loci. It is therefore possible that noncoding regulatory variants within these loci or yet unidentified loci could be the cause of RLS in our families.
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http://dx.doi.org/10.1212/NXG.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305992PMC
December 2018

Whole exome sequencing identifies novel predisposing genes in neural tube defects.

Mol Genet Genomic Med 2019 01 10;7(1):e00467. Epub 2018 Nov 10.

IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Background: Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown.

Methods: We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches.

Results: We identified four novel loss-of-function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD.

Conclusion: These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next-generation sequencing in deciphering the genetics of this complex trait.
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http://dx.doi.org/10.1002/mgg3.467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382446PMC
January 2019

Triple A syndrome presenting as complicated hereditary spastic paraplegia.

Mol Genet Genomic Med 2018 11 31;6(6):1134-1139. Epub 2018 Oct 31.

Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Background: Hereditary spastic paraplegia (HSP) is a group of rare disorders characterized by spastic paraparesis and other symptoms. Often, other diseases can mimic HSP, which may delay diagnosis and treatment.

Methods: Whole exome sequencing was performed in families with clinically suspected HSP without a genetic diagnosis.

Results: We report three patients from two families who presented with lower limb spasticity, muscular atrophy, and other neurological symptoms, who were clinically diagnosed with complicated HSP. Whole exome sequencing revealed bi-allelic AAAS nonsense mutations; one individual was homozygous for the p.(Arg478*) mutation, and two siblings were homozygous for the p.(Arg286*) mutation, leading to the diagnosis of triple A syndrome. This rare syndrome is typically characterized by a triad of symptoms: achalasia, adrenal insufficiency, and alacrima, and is often accompanied by other neurological abnormalities.

Conclusions: Our findings suggest that triple A syndrome should be suspected in complicated HSP patients without a known genetic cause, especially if at least one of the main triad of triple A syndrome symptoms is present.
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http://dx.doi.org/10.1002/mgg3.492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305671PMC
November 2018

Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males.

Am J Med Genet B Neuropsychiatr Genet 2019 09 30;180(6):335-340. Epub 2018 Oct 30.

Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.
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http://dx.doi.org/10.1002/ajmg.b.32683DOI Listing
September 2019

Non-invasive prenatal aneuploidy testing: Critical diagnostic performance parameters predict sample z-score values.

Clin Biochem 2018 Sep 27;59:69-77. Epub 2018 Jun 27.

Service of Medical Biochemistry, Department of Medical Biology, CHU de Québec - Université Laval, Quebec, Canada; Department of Molecular Biology, Medical Biochemistry, and Pathology, Faculty of Medicine, Université Laval, Quebec, Canada; Human and Molecular Genetics Research Unit, Research Center, CHU de Québec, Quebec, Canada; PEGASUS, Quebec, Canada.

Objectives: Non-invasive prenatal aneuploidy testing (NIPT) by next-generation sequencing of circulating cell-free DNA in maternal plasma relies on chromosomal ratio (chr) measurements to detect aneuploid values that depart from euploid ratios. Diagnostic performances are known to depend on the fraction of fetal DNA (FF) present in maternal plasma, although how this translates into specific quantitative changes in specificity/positive predictive values and which other variables might also be important is not well understood.

Design & Methods: To explore this issue, theoretical relationships between FF and various measures of diagnostic performances were assessed for a range of parameter values. Empirical data from three NIPT assays were then used to validate theoretical calculations.

Results: For a given positivity threshold, dramatic changes in specificity and positive predictive values (PPV) as a function of both FF and the coefficient of variation (CV) of the chr measurement were observed. Theoretically predicted and observed chr z-scores agreed closely, confirming the determinant impact of small changes in both FF and chr CV.

Conclusions: Evaluation of NIPT assay performances therefore requires knowledge of the FF distribution in the population in which the test is intended to be used and, in particular, of the precise value of the assay chr CV for each chromosome or genomic region of interest. Laboratories offering NIPT testing should carefully measure these parameters to ensure test reliability and clinical usefulness in interpreting individual patients' results.
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http://dx.doi.org/10.1016/j.clinbiochem.2018.06.015DOI Listing
September 2018

Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia.

Mol Psychiatry 2020 04 12;25(4):821-830. Epub 2018 Jun 12.

Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium-potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.
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http://dx.doi.org/10.1038/s41380-018-0103-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291354PMC
April 2020

Identification of a rare pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing.

Hum Genome Var 2018 8;5:18001. Epub 2018 Mar 8.

Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 () was discovered. In the human brain tissue, immunofluorescent staining demonstrated a vascular predominance of SMAD9 at the protein level. Vascular SMAD9 was markedly reduced in AVM peri-nidal blood vessels, which was accompanied by a decrease in phosphorylated SMAD4, a downstream effector protein of the bone morphogenic protein signaling pathway. Zebrafish modeling () of the morpholino splice site and translation-blocking knockdown of resulted in abnormal cerebral artery-to-vein connections with morphologic similarities to human AVMs. Orthogonal trajectories of evidence established a relationship between the candidate mutation discovered in via WES and the clinical phenotype. Replication in similar rare cases of recurrent AVM, or even more broadly sporadic AVM, may be informative in building a more comprehensive understanding of AVM pathogenesis.
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http://dx.doi.org/10.1038/hgv.2018.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966745PMC
March 2018

Correction to: Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report.

BMC Pediatr 2018 04 17;18(1):138. Epub 2018 Apr 17.

Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Mohammed V University in Rabat, Rabat, Morocco.

After publication of the original article [1] it was brought to our attention that author Bouchra Ouled Amar Bencheikh was incorrectly included as Bouchra Oulad Amar Bencheikh.
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http://dx.doi.org/10.1186/s12887-018-1114-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905117PMC
April 2018

Global characterization of copy number variants in epilepsy patients from whole genome sequencing.

PLoS Genet 2018 04 12;14(4):e1007285. Epub 2018 Apr 12.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Canada.

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases.
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http://dx.doi.org/10.1371/journal.pgen.1007285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978987PMC
April 2018

Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population.

Sci Rep 2018 03 12;8(1):4356. Epub 2018 Mar 12.

Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.

Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10), the one at 3q13.2 (rs78125721, p = 4.77 × 10), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.
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http://dx.doi.org/10.1038/s41598-018-21603-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847615PMC
March 2018

Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report.

BMC Pediatr 2018 02 27;18(1):90. Epub 2018 Feb 27.

Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Mohammed V University in Rabat, Rabat, Morocco.

Background: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis.

Case Presentation: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family.

Conclusion: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.
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http://dx.doi.org/10.1186/s12887-018-1063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830319PMC
February 2018

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.

Am J Hum Genet 2017 Nov;101(5):664-685

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673604PMC
November 2017

Functionally Null Missense Mutation Associates Strongly with Ovarian Carcinoma.

Cancer Res 2017 08 23;77(16):4517-4529. Epub 2017 Jun 23.

Department of Human Genetics, McGill University, Montreal, Canada.

RAD51D is a key player in DNA repair by homologous recombination (HR), and truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense variants. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0190DOI Listing
August 2017

Rare deleterious variants in GRHL3 are associated with human spina bifida.

Hum Mutat 2017 06 24;38(6):716-724. Epub 2017 Mar 24.

CHU Sainte Justine Research Center and University of Montréal, Montréal, Québec, Canada.

Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.
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http://dx.doi.org/10.1002/humu.23214DOI Listing
June 2017

RIC3 variants are not associated with Parkinson's disease in French-Canadians and French.

Neurobiol Aging 2017 05 11;53:194.e9-194.e11. Epub 2017 Jan 11.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada. Electronic address:

Variants in the RIC3 gene have recently been suggested as a novel cause of Parkinson's disease (PD). Herein, the entire RIC3 gene was sequenced in a French-Canadian and French sample series of 535 PD patients and 527 unaffected controls. The effect of single variants and the combined effect of variants were calculated. Sequence Kernel association tests (SKAT, SKAT-O) were done on the entire gene level, and on the different domains and exons of RIC3. A total of 28 common and rare variants were identified in patients and controls. No significant association was found between any variant and haplotype in RIC3 and PD, and there was no over-representation of RIC3 variants at the entire gene, domain, or exon levels in patients versus controls. Our results do not support a role for RIC3 mutations as a common cause of PD in the French-Canadian and French populations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.01.005DOI Listing
May 2017

Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails.

J Hum Genet 2017 Apr 22;62(4):465-471. Epub 2016 Dec 22.

CHU-Sainte Justine Research Centre, University of Montreal, Montreal, Quebec, Canada.

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.
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http://dx.doi.org/10.1038/jhg.2016.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370204PMC
April 2017

RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population.

Am J Hum Genet 2016 Nov 13;99(5):1072-1085. Epub 2016 Oct 13.

Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada. Electronic address:

Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.
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http://dx.doi.org/10.1016/j.ajhg.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097946PMC
November 2016

SYNE1 mutations cause autosomal-recessive ataxia with retained reflexes in Brazilian patients.

Mov Disord 2016 11 27;31(11):1754-1756. Epub 2016 Sep 27.

Division of General Neurology and Ataxia Unit, Department of Neurology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.

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http://dx.doi.org/10.1002/mds.26810DOI Listing
November 2016
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