Publications by authors named "Marie Vincent"

65 Publications

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder.

Genet Med 2021 Aug 3. Epub 2021 Aug 3.

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics.

Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature.

Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice.

Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
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http://dx.doi.org/10.1038/s41436-021-01263-1DOI Listing
August 2021

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.

Genet Med 2021 Jun 23. Epub 2021 Jun 23.

Rare Diseases and Medical Genetic Unit, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Purpose: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.

Methods: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.

Results: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.

Conclusion: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
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http://dx.doi.org/10.1038/s41436-021-01232-8DOI Listing
June 2021

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

J Med Genet 2021 Apr 5. Epub 2021 Apr 5.

Department of Pediatric Neurology, APHP-Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.

Methods: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.

Results: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (, , , , , , , and ). Moreover, we identified pathogenic variants in and expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).

Conclusion: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
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http://dx.doi.org/10.1136/jmedgenet-2020-107595DOI Listing
April 2021

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

Am J Hum Genet 2021 05 2;108(5):929-941. Epub 2021 Apr 2.

Etablissement Français du Sang, 44000 Nantes, France; CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44000 Nantes, France; LabEx IGO, Nantes 44000, France.

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206166PMC
May 2021

ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes.

J Inherit Metab Dis 2021 Jul 26;44(4):1001-1012. Epub 2021 Mar 26.

Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13-CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13-CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N-linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.
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http://dx.doi.org/10.1002/jimd.12378DOI Listing
July 2021

Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort.

J Neurol 2021 Sep 5;268(9):3337-3343. Epub 2021 Mar 5.

Department of Neurology, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg, France.

Objective: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).

Methods: 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.

Results: A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.

Conclusion: Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
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http://dx.doi.org/10.1007/s00415-021-10499-5DOI Listing
September 2021

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.

Eur J Hum Genet 2021 Apr 12;29(4):625-636. Epub 2021 Jan 12.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
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http://dx.doi.org/10.1038/s41431-020-00769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115148PMC
April 2021

Screening of a Large Cohort of Asymptomatic SDHx Mutation Carriers in Routine Practice.

J Clin Endocrinol Metab 2021 03;106(3):e1301-e1315

Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols.

Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.

Design And Setting: Retrospective multicentric study in 6 referral centers.

Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled.

Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.

Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data.
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http://dx.doi.org/10.1210/clinem/dgaa888DOI Listing
March 2021

Prevalence of Immunological Defects in a Cohort of 97 Rubinstein-Taybi Syndrome Patients.

J Clin Immunol 2020 08 27;40(6):851-860. Epub 2020 Jun 27.

Departamento de Nefrología, Hospital Universitario de Santiago, Santiago de Compostela, Spain.

Although recurrent infections in Rubinstein-Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. Graphical Abstract.
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http://dx.doi.org/10.1007/s10875-020-00808-4DOI Listing
August 2020

Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation.

Genet Med 2020 11 22;22(11):1887-1891. Epub 2020 Jun 22.

Service de Génétique Clinique, CHU de Dijon, Dijon, France.

Purpose: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC).

Methods: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered.

Results: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy.

Conclusion: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.
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http://dx.doi.org/10.1038/s41436-020-0872-8DOI Listing
November 2020

Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation.

Nat Commun 2020 05 7;11(1):2243. Epub 2020 May 7.

Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108, Freiburg, Germany.

Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states.
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http://dx.doi.org/10.1038/s41467-020-16103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206058PMC
May 2020

Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development.

Neuron 2020 05 4;106(3):404-420.e8. Epub 2020 Mar 4.

APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France.

De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.
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http://dx.doi.org/10.1016/j.neuron.2020.01.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331285PMC
May 2020

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):338-355. Epub 2020 Feb 27.

Developmental Brain Disorders Laboratory, INSERM UMR 1163, 75015 Paris, France; Service de Génétique, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Pairs, 75015 Paris, France.

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058823PMC
March 2020

Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20.

Eur J Hum Genet 2020 08 18;28(8):1044-1055. Epub 2020 Feb 18.

Unité de Génétique Chromosomique ou Cytogénétique, Centre Hospitalier Universitaire de Nantes, Nantes, France.

Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
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http://dx.doi.org/10.1038/s41431-020-0582-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382504PMC
August 2020

Variable neurodevelopmental and morphological phenotypes of carriers with 12q12 duplications.

Mol Genet Genomic Med 2020 01 15;8(1):e1013. Epub 2019 Nov 15.

Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Child and Adolescent Psychiatry, Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.

Background: Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal duplications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature.

Methods: We report a phenotypic description of a family with monozygotic twins diagnosed with NDDs, carrying a 9 Mb duplication at 12q12, and five other individuals with overlapping duplications ranging from 4.54 Mb up to 15.16 Mb.

Results: The duplication carriers had language delays, cognitive delays, and were diagnosed with autism spectrum disorder. Additionally, distinct facial features (e.g., high foreheads, deeply set eyes, short palpebral fissures, small ears, high nasal bridges, abnormalities of the nose tip, thin lips), large feet, and abnormalities in the digits were noted. We also describe incomplete penetrance of the NDD phenotypes among the individuals with 12q12 duplication.

Conclusion: This case series expands our knowledge on this rare genetic aberration and suggests that large 12q12 duplications may increase the risk for developing NDDs.
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http://dx.doi.org/10.1002/mgg3.1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978403PMC
January 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4.

Genet Med 2020 03 24;22(3):547-556. Epub 2019 Oct 24.

Service de Génétique Clinique, centre de référence anomalies du développement et syndromes malformatifs, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, Faculté de Médecine, Montpellier, France.

Purpose: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.

Methods: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.

Results: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives.

Conclusion: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.
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http://dx.doi.org/10.1038/s41436-019-0669-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056642PMC
March 2020

Identification of Mutations in SDR9C7 in Three Patients with Autosomal Recessive Congenital Ichthyosis.

Acta Derm Venereol 2020 02 5;100(4). Epub 2020 Feb 5.

Dermatology Department, Reference Center for Rare Skin Diseases, CHU Larrey, Université Paul Sabatier, FR-31000 Toulouse, France.

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http://dx.doi.org/10.2340/00015555-3359DOI Listing
February 2020

Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders.

Am J Respir Crit Care Med 2019 11;200(9):1093-1101

Department of Molecular and Human Genetics and.

Lethal lung developmental disorders are a rare but important group of pediatric diffuse lung diseases presenting with neonatal respiratory failure. On the basis of histopathological appearance at lung biopsy or autopsy, they have been termed: alveolar capillary dysplasia with misalignment of the pulmonary veins, acinar dysplasia, congenital alveolar dysplasia, and other unspecified primary pulmonary hypoplasias. However, the histopathological continuum in these lethal developmental disorders has made accurate diagnosis challenging, which has implications for recurrence risk. Over the past decade, genetic studies in infants with alveolar capillary dysplasia with misalignment of the pulmonary veins have revealed the causative role of the dosage-sensitive gene and its noncoding regulatory variants in the distant lung-specific enhancer at chromosome 16q24.1. In contrast, the molecular bases of acinar dysplasia and congenital alveolar dysplasia have remained poorly understood. Most recently, disruption of the TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling pathway has been reported in patients with these lethal pulmonary dysplasias. Application of next-generation sequencing techniques, including exome sequencing and whole-genome sequencing, has demonstrated their complex compound inheritance. These data indicate that noncoding regulatory elements play a critical role in lung development in humans. We propose that for more precise lethal lung developmental disorder diagnosis, a diagnostic pathway including whole-genome sequencing should be implemented.
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http://dx.doi.org/10.1164/rccm.201903-0495TRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888654PMC
November 2019

Autosomal recessive Treacher Collins syndrome due to POLR1C mutations: Report of a new family and review of the literature.

Am J Med Genet A 2019 07 8;179(7):1390-1394. Epub 2019 Apr 8.

Service de Génétique Médicale, CHU Nantes, Nantes, France.

Treacher Collins syndrome (TCS) is a frequent cause of mandibulofacial dysostosis. To date, TCS-causing mutations in three genes, namely TCOF1, POLR1D, and POLR1C have been identified. TCS is usually inherited in an autosomal dominant manner, with a high clinical variability and no phenotype-genotype correlation. Up-to now, five families have been reported with an autosomal recessive mode of inheritance due to mutations in POLR1D or POLR1C. We report here a new family with two sisters affected by mild TCS carrying compound POLR1C heterozygous mutations, and review the literature on mild forms of TCS, autosomal recessive inheritance in this syndrome and POLR1C mutations.
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http://dx.doi.org/10.1002/ajmg.a.61147DOI Listing
July 2019

Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes.

Mol Med 2019 02 27;25(1). Epub 2019 Feb 27.

Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Zurich, Switzerland.

Background: Deleterious variants in the voltage-gated sodium channel type 2 (Na1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood.

Methods: To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling.

Results: The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings.

Conclusions: Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Na1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.
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http://dx.doi.org/10.1186/s10020-019-0073-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391808PMC
February 2019

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

Genet Med 2019 09 6;21(9):2025-2035. Epub 2019 Feb 6.

Centre de Genetique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs de l'Est, FHU-TRANSLAD, CHU Dijon, Dijon, France.

Purpose: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.

Methods: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay.

Results: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance.

Conclusion: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
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http://dx.doi.org/10.1038/s41436-019-0445-xDOI Listing
September 2019

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

Delineating syndrome: From congenital microcephaly to hyperkinetic encephalopathy.

Neurol Genet 2018 Dec 7;4(6):e281. Epub 2018 Nov 7.

Objective: To provide new insights into the related clinical and imaging phenotypes and refine the phenotype-genotype correlation in syndrome.

Methods: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic variant and performed phenotype-genotype correlations.

Results: A total of 37 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of , which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.

Conclusions: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.
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http://dx.doi.org/10.1212/NXG.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244024PMC
December 2018

A de novo 2q37.2 deletion encompassing AGAP1 and SH3BP4 in a patient with autism and intellectual disability.

Eur J Med Genet 2019 Dec 22;62(12):103586. Epub 2018 Nov 22.

CHU Nantes, Service de Génétique Médicale, Nantes, France; INSERM, UMR 1238, Bone Sarcoma and Remodeling of Calcified Tissue, Nantes, France.

Autism spectrum disorders are complex neurodevelopmental syndromes characterized by phenotypic and genetic heterogeneity. Further identification of causal genes may help in better understanding the underlying mechanisms of the disorder, thus improving the patients' management. To date, abnormal synaptogenesis is thought to be one of the major underlying causes of autism spectrum disorders. Here, using oligoarray-based comparative genomic hybridization, we identified a de novo deletion at 2q37.2 locus spanning 1 Mb and encompassing AGAP1 and SH3BP4, in a boy with autism and intellectual disability. Both genes have been described as being involved in endosomal trafficking, and AGAP1 in particular has been shown to be expressed in the developing brain and to play a role in dendritic spine formation and synapse function, making it a potential causative gene to our patient's phenotype.
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http://dx.doi.org/10.1016/j.ejmg.2018.11.020DOI Listing
December 2019

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

Genet Med 2019 04 7;21(4):816-825. Epub 2018 Sep 7.

CHU Nantes, Medical genetics department, Nantes, France.

Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.

Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.

Results: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.

Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.
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http://dx.doi.org/10.1038/s41436-018-0266-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405313PMC
April 2019

Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.

Eur J Med Genet 2019 Jun 22;62(6):103530. Epub 2018 Aug 22.

Service de Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, INSERM U1211, Univ. Bordeaux, Bordeaux, France; Centre de Référence Neurogénétique, Service de Génétique Médicale, CHU de Bordeaux, France.

The CACNA1A gene encodes a calcium-dependent voltage channel, localized in neuronal cells. Pathogenic variants in this gene are known to lead to a broad clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We report a large family revealing a wide variability of neurological manifestations associated with a CACNA1A missense pathogenic variant. The index case had early-onset epileptic encephalopathy with progressive cerebellar atrophy, although his mother and his great-grandmother suffered from paroxystic episodic ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her sons displayed early-onset ataxia with intellectual disability. Two of her little daughters suffered from gait disorders, and also from epilepsy for one of them. All these relatives were carriers of the previously described heterozygous variant in CACNA1A gene. We report here the first family leading to major clinical variability and incomplete penetrance. Our family highlights the difficulties to provide accurate genetic counselling concerning prenatal diagnosis regarding highly variable severity of the clinical presentation.
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http://dx.doi.org/10.1016/j.ejmg.2018.08.011DOI Listing
June 2019
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