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1.
Hum Genomics ; 17(1): 16, 2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36859317

RESUMEN

BACKGROUND: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. MATERIALS AND METHODS: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. RESULTS: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. CONCLUSION: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.


Asunto(s)
Hidrocefalia , Herencia Multifactorial , Femenino , Embarazo , Humanos , Mutación , Consanguinidad , Bases de Datos Factuales
2.
Neurodegener Dis ; 24(1): 16-25, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38763140

RESUMEN

INTRODUCTION: Subjective cognitive decline (SCD) is characterized by subjective cognitive concerns without objective cognitive impairment and is considered a risk factor for cognitive decline and dementia. However, most SCD patients will not develop neurodegenerative disorders, yet they may suffer from minor psychiatric, neurological, or somatic comorbidities. The aim of the present study was to provide a taxonomy of the heterogeneous SCD entity and to conduct a preliminary validation using data from a memory clinic sample. METHODS: Participants were fifty-five SCD individuals consecutively recruited at the Geneva Memory Center. Based on clinical reports, they were classified into three clinically pre-defined subgroups: (i) those with psychological or psychiatric comorbidities (Psy), (ii) those with somatic comorbidities (SomCom), (iii) and those with no apparent cause (NAC). Baseline demographics, clinical, cognitive, and biomarker differences among the SCD subgroups were assessed. Longitudinal cognitive changes (average 3 years follow-up) were modeled using a linear mixed model. RESULTS: Out of the 55 SCD cases, 16 were SomCom, 18 Psy, and 21 NAC. 47% were female, mean age was 71 years. We observed higher frequency of APOE ε4 carriers in NAC (53%) compared to SomCom (14%) and Psy (0%, p = 0.023) and lower level of plasma Aß42 in NAC (6.8 ± 1.0) compared to SomCom (8.4 ± 1.1; p = 0.031). SomCom subjects were older (74 years) than Psy (67 years, p = 0.011), and had greater medial temporal lobe atrophy (1.0 ± 1.0) than Psy (0.2 ± 0.6) and NAC (0.4 ± 0.5, p = 0.005). SomCom has worse episodic memory performances (14.5 ± 3.5) than Psy (15.8 ± 0.4) and NAC (15.8 ± 0.7, p = 0.032). We observed a slightly steeper, yet not statistically significant, cognitive decline in NAC (ß = -0.48) compared to Psy (ß = -0.28) and SomCom (ß = -0.24). CONCLUSIONS: NAC features a higher proportion of APOE ε4 carriers, lower plasma Aß42 and a trend towards steeper cognitive decline than SomCom and Psy. Taken together, these findings suggest that NACs are at higher risk of cognitive decline due to AD. The proposed clinical taxonomy might be implemented in clinical practice to identify SCD at higher risk. However, such taxonomy should be tested on an independent cohort with a larger sample size.


Asunto(s)
Disfunción Cognitiva , Humanos , Femenino , Masculino , Anciano , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/sangre , Persona de Mediana Edad , Estudios de Cohortes , Pruebas Neuropsicológicas/estadística & datos numéricos , Anciano de 80 o más Años , Péptidos beta-Amiloides/sangre , Apolipoproteína E4/genética , Autoevaluación Diagnóstica
3.
Hum Mol Genet ; 29(23): 3757-3764, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33205811

RESUMEN

Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.


Asunto(s)
Feto/patología , Hidrocefalia/patología , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Receptor trkA/metabolismo , Femenino , Feto/metabolismo , Homocigoto , Humanos , Hidrocefalia/etiología , Hidrocefalia/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Malformaciones del Sistema Nervioso/etiología , Malformaciones del Sistema Nervioso/metabolismo , Linaje , Receptor trkA/genética
4.
Clin Genet ; 104(5): 505-515, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37434539

RESUMEN

Noninvasive prenatal diagnosis relies on the presence in maternal blood of circulating cell-free fetal DNA released by apoptotic trophoblast cells. Widely used for aneuploidy screening, it can also be applied to monogenic diseases (NIPD-M) in case of known parental mutations. Due to the confounding effect of maternal DNA, detection of maternal or biparental mutations requires relative haplotype dosage (RHDO), a method relying on the presence of SNPs that are heterozygous in one parent and homozygous in the other. Unavoidably, there is a risk of test failure by lack of such informative SNPs, an event particularly likely for consanguineous couples who often share common haplotypes in regions of identity-by-descent. Here we present a novel approach, relative genotype dosage (RGDO) that bypasses this predicament by directly assessing fetal genotype with SNPs that are heterozygous in both parents (frequent in regions of identity-by-descent). We show that RGDO is as sensitive as RHDO and that it performs well over a large range of fetal fractions and DNA amounts, thereby opening NIPD-M to most consanguineous couples. We also report examples of couples, consanguineous or not, where combining RGDO and RHDO allowed a diagnosis that would not have been possible with only one approach.


Asunto(s)
Pruebas Prenatales no Invasivas , Embarazo , Femenino , Humanos , Diagnóstico Prenatal/métodos , Consanguinidad , Genotipo , ADN/genética
5.
Clin Genet ; 103(3): 346-351, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36371792

RESUMEN

Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the "AP4 deficiency syndrome." Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012C>T p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single-nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.


Asunto(s)
Epilepsia , Discapacidad Intelectual , Paraplejía Espástica Hereditaria , Humanos , Discapacidad Intelectual/genética , Mutación/genética , Efecto Fundador , Paraplejía/genética , Paraplejía Espástica Hereditaria/genética , Epilepsia/genética , Linaje , Fenotipo
6.
Rev Med Suisse ; 19(848): 2073-2079, 2023 Nov 01.
Artículo en Francés | MEDLINE | ID: mdl-37910058

RESUMEN

Genetic analysis using high-throughput sequencing is a powerful tool for patients with rare diseases. However, biological and clinical interpretation thereof is difficult, especially when the clinical picture is complex. Multidisciplinary Genome Boards bring together the relevant medical specialties around the patient's medical and genetic file, to optimize the correlation between phenotype and genotype. This often allows the identification of the causal genetic variant in previously unsolved cases. A retrospective study shows that Genome Boards significantly increase the diagnostic rate in complex clinical cases with difficult-to-interpret genetic analysis results, as well as facilitating collaboration between the various medical specialties involved.


Les analyses génétiques par séquençage à haut débit sont un outil puissant pour les patients atteints de maladies rares. Leurs interprétations biologique et clinique sont cependant difficiles, et cela d'autant plus que le tableau clinique est complexe. Les genome boards multidisciplinaires réunissent les spécialités médicales pertinentes autour du dossier médical et génétique du patient, afin d'optimiser la corrélation entre le phénotype et le génotype. Ceci permet souvent d'identifier le variant génétique causal dans des cas jusque-là non élucidés. Une étude rétrospective montre que les genome boards permettent d'augmenter le taux de diagnostic moléculaire pour des cas cliniques complexes avec des résultats d'analyses difficiles à interpréter, en plus de faciliter la collaboration entre les différentes spécialités médicales impliquées.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Pacientes , Humanos , Estudios Retrospectivos , Genotipo , Estudios Interdisciplinarios
7.
Hum Genet ; 141(11): 1697-1704, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35488921

RESUMEN

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.


Asunto(s)
Predisposición Genética a la Enfermedad , Medicina Genómica , Genómica , Humanos , Herencia Multifactorial/genética , Factores de Riesgo
8.
Hum Mutat ; 42(4): 373-377, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33492714

RESUMEN

Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported in the literature but never fully described nor their pathogenicity assessed. Here, we report two unrelated patients with moderate hearing-loss, who were compound heterozygotes for a converted allele and a deletion of OTOA. The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome sequencing, then confirmed with long range polymerase chain reactions. Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*). Using genomic alignments and long read nanopore sequencing, we found that the two probands carry stretches of converted DNA of widely different lengths (at least 9 kbp and around 900 bp, respectively).


Asunto(s)
Sordera , Proteínas Ligadas a GPI , Pérdida Auditiva , Alelos , Sordera/genética , Proteínas Ligadas a GPI/genética , Conversión Génica , Pérdida Auditiva/genética , Humanos , Linaje , Secuenciación del Exoma
9.
Genet Med ; 23(11): 2150-2159, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34345024

RESUMEN

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.


Asunto(s)
Discapacidad Intelectual , Microcefalia , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Animales , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Ratones , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Quinasas DyrK
10.
Clin Genet ; 100(3): 329-333, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34037256

RESUMEN

Arthrogryposis describes the presence of multiple joint-contractures. Clinical severity of this phenotype is variable, and more than 400 causative genes have been proposed. Among these, ERGIC1 is a recently reported candidate encoding a putative transmembrane protein of the ER-Golgi interface. Two homozygous missense variants have been reported in patients with relatively mild non-syndromic arthrogryposis. In a consanguineous family with two affected siblings presenting congenital arthrogryposis and some facial dysmorphism we performed prenatal array-CGH, postnatal targeted exome and genome sequencing. Genome sequencing identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents. Our observations validate the pathogenic role of ERGIC1 in congenital arthrogryposis and demonstrate that complete loss of function causes a relatively mild phenotype. These findings will contribute to improve genetic counseling of ERGIC1 mutations.


Asunto(s)
Artrogriposis/genética , Proteínas de Transporte Vesicular/genética , Consanguinidad , Homocigoto , Humanos , Lactante , Mutación con Pérdida de Función , Pérdida de Heterocigocidad , Masculino , Regiones Promotoras Genéticas/genética , Análisis por Matrices de Proteínas , ARN Mensajero , Secuenciación del Exoma
11.
Hum Mutat ; 41(2): 512-524, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31696992

RESUMEN

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM.


Asunto(s)
Centrosoma/metabolismo , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Patrón de Herencia , Microcefalia/diagnóstico , Microcefalia/genética , Animales , Bases de Datos Genéticas , Estudios de Asociación Genética/métodos , Humanos , Mutación , Sistemas de Lectura Abierta , Fenotipo , Transducción de Señal , Secuenciación del Exoma , Pez Cebra
12.
Semin Cell Dev Biol ; 76: 76-85, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28912110

RESUMEN

Primary microcephaly (PM) refers to a congenitally small brain, resulting from insufficient prenatal production of neurons, and serves as a model disease for brain volumic development. Known PM genes delineate several cellular pathways, among which the centriole duplication pathway, which provide interesting clues about the cellular mechanisms involved. The general interest of the genetic dissection of PM is illustrated by the convergence of Zika virus infection and PM gene mutations on congenital microcephaly, with CENPJ/CPAP emerging as a key target. Physical (protein-protein) and genetic (digenic inheritance) interactions of Wdr62 and Aspm have been demonstrated in mice, and should now be sought in humans using high throughput parallel sequencing of multiple PM genes in PM patients and control subjects, in order to categorize mutually interacting genes, hence delineating functional pathways in vivo in humans.


Asunto(s)
Encéfalo/patología , Microcefalia/genética , Malformaciones del Sistema Nervioso/genética , Humanos , Microcefalia/patología , Mutación , Malformaciones del Sistema Nervioso/patología
13.
BMC Med Genet ; 21(1): 109, 2020 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-32423379

RESUMEN

BACKGROUND: Perrault syndrome is a rare recessive and genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and gonadal dysgenesis in females. Mutations in seven different genes have been identified: HARS2, HSD17B4, CLLP, C10orf, ERAL1, TWNK and LARS2. To date, 19 variants have been reported in 18 individuals with LARS2-Perrault syndrome. CASE PRESENTATION: Here we describe the case of an 8-year-old girl with compound heterozygous missense mutations in the LARS2 gene. We identified two missense mutations [c.457A > C, p.(Asn153His) and c.1565C > A, p.(Thr522Asn)] and subsequent familial segregation showed that each parent had transmitted a mutation. CONCLUSIONS: These results have implications for genetic counseling and provide insight into the functional role of LARS2. This case highlights the importance of an early diagnosis. Systematic genetic screening of children with hearing loss allows the early identification of a Perrault syndrome in order to ensure specific endocrinological surveillance and management to prevent secondary complications. Clinical data are compared with the other cases reported in the literature.


Asunto(s)
Aminoacil-ARNt Sintetasas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/genética , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Mutación , Alelos , Sustitución de Aminoácidos , Biomarcadores , Niño , Manejo de la Enfermedad , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Disgenesia Gonadal 46 XX/terapia , Pérdida Auditiva Sensorineural/terapia , Humanos , Fenotipo
14.
Gastroenterology ; 154(8): 2165-2177, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29501442

RESUMEN

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.


Asunto(s)
Enfermedad de Crohn/genética , Síndromes de Inmunodeficiencia/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Células Cultivadas , Niño , Preescolar , Enfermedad de Crohn/sangre , Enfermedad de Crohn/inmunología , Femenino , Técnica del Anticuerpo Fluorescente , Francia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/inmunología , Interleucina-10/genética , Masculino , Persona de Mediana Edad , Monocitos , Mutación Missense , Proteína Adaptadora de Señalización NOD2/metabolismo , Cultivo Primario de Células , Análisis de Secuencia de ADN , Transducción de Señal/genética , Adulto Joven
15.
Rev Med Suisse ; 15(665): 1740-1745, 2019 Oct 02.
Artículo en Francés | MEDLINE | ID: mdl-31580017

RESUMEN

The majority of early hearing disorders are of genetic origin. In view of the genetic heterogeneity, high-throughput sequencing analysis of a panel of genes involved in hearing loss is the most effective and economical approach, providing a diagnostic yield of around 40 % today. The determination of a molecular diagnosis makes it possible to: i) adapt the audiological care; ii) to search for possible somatic problems associated with so-called syndromic hearing loss; (iii) to avoid unnecessary additional examinations in isolated hearing loss; (iv) to establish accurate genetic counseling for relatives, or even to provide early diagnosis; and (v) to lay the foundation for potential future molecular hearing loss therapies in selected cases.


La majorité des troubles auditifs précoces est d'origine génétique. La détection rapide et la prise en charge adaptée limitent l'impact développemental; de même, un diagnostic étiologique précis améliore le suivi des patients. Au vu de l'hétérogénéité génétique des troubles auditifs, l'analyse par séquençage à haut débit d'un panel de gènes constitue l'approche la plus efficace et économique avec un rendement actuel d'environ 40 %. Le diagnostic moléculaire permet: 1) d'adapter la prise en charge audiologique; 2) de rechercher d'éventuels problèmes somatiques associés; 3) d'éviter des examens complémentaires inutiles dans les déficits auditifs isolés; 4) d'établir un conseil génétique pour les apparentés, voire de proposer un diagnostic précoce; 5) d'établir les bases d'une éventuelle thérapie génique future.


Asunto(s)
Pérdida Auditiva/genética , Niño , Sordera/diagnóstico , Sordera/genética , Sordera/terapia , Diagnóstico Precoz , Asesoramiento Genético , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/terapia , Humanos , Terapia Molecular Dirigida , Síndrome
16.
Hum Mutat ; 39(3): 319-332, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29243349

RESUMEN

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.


Asunto(s)
Microcefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Preescolar , Cognición , Estudios de Cohortes , Familia , Femenino , Estudios de Asociación Genética , Geografía , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Microcefalia/epidemiología
17.
Nucleic Acids Res ; 44(D1): D900-7, 2016 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-26481352

RESUMEN

DIDA (DIgenic diseases DAtabase) is a novel database that provides for the first time detailed information on genes and associated genetic variants involved in digenic diseases, the simplest form of oligogenic inheritance. The database is accessible via http://dida.ibsquare.be and currently includes 213 digenic combinations involved in 44 different digenic diseases. These combinations are composed of 364 distinct variants, which are distributed over 136 distinct genes. The web interface provides browsing and search functionalities, as well as documentation and help pages, general database statistics and references to the original publications from which the data have been collected. The possibility to submit novel digenic data to DIDA is also provided. Creating this new repository was essential as current databases do not allow one to retrieve detailed records regarding digenic combinations. Genes, variants, diseases and digenic combinations in DIDA are annotated with manually curated information and information mined from other online resources. Next to providing a unique resource for the development of new analysis methods, DIDA gives clinical and molecular geneticists a tool to find the most comprehensive information on the digenic nature of their diseases of interest.


Asunto(s)
Bases de Datos Genéticas , Enfermedad/genética , Herencia Multifactorial , Genes , Variación Genética , Humanos , Anotación de Secuencia Molecular
18.
Rev Med Suisse ; 14(619): 1666-1669, 2018 Sep 19.
Artículo en Francés | MEDLINE | ID: mdl-30230775

RESUMEN

The multidiscipinary care of patients with intellectual disability requires a structured and systematic etiological process. Today, advances in technology make it possible to perform diagnostic genetic analyzes that are highly contributive in this process. The CGH-array (Comparative Genomic Hybridization array) makes it possible to search for chromosomal anomalies with a very high level of resolution; high throughput sequencing can detect gene abnormalities on the whole exome or on a panel of genes. For the patient the detection of genetic anomalies aims to improve the quality of care; for related parties, genetic counseling is systematically offered.


La prise en charge multidisciplinaire des patients présentant un handicap intellectuel impose la mise en œuvre d'une démarche étiologique structurée et systématique. Les avancées technologiques permettent aujourd'hui la réalisation d'analyses génétiques diagnostiques très contributives. Le CGH-array (puce d'hybridation génomique comparative) permet de rechercher des anomalies chromosomiques avec un très haut niveau de résolution; le séquençage à haut débit permet de détecter des anomalies géniques sur l'exome entier ou sur un panel de gènes. Pour le patient, la détection d'anomalies génétiques a pour objectif d'améliorer la qualité de la prise en charge; pour les apparentés, un conseil génétique est systématiquement proposé.


Asunto(s)
Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Discapacidad Intelectual , Asesoramiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/genética
19.
Hum Mol Genet ; 24(10): 2771-83, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25652408

RESUMEN

Dymeclin is a Golgi-associated protein whose deficiency causes Dyggve-Melchior-Clausen syndrome (DMC, MIM #223800), a rare recessively inherited spondyloepimetaphyseal dysplasia consistently associated with postnatal microcephaly and intellectual disability. While the skeletal phenotype of DMC patients has been extensively described, very little is known about their cerebral anomalies, which result in brain growth defects and cognitive dysfunction. We used Dymeclin-deficient mice to determine the cause of microcephaly and to identify defective mechanisms at the cellular level. Brain weight and volume were reduced in all mutant mice from postnatal day 5 onward. Mutant mice displayed a narrowing of the frontal cortex, although cortical layers were normally organized. Interestingly, the corpus callosum was markedly thinner, a characteristic we also identified in DMC patients. Consistent with this, the myelin sheath was thinner, less compact and not properly rolled, while the number of mature oligodendrocytes and their ability to produce myelin basic protein were significantly decreased. Finally, cortical neurons from mutant mice and primary fibroblasts from DMC patients displayed substantially delayed endoplasmic reticulum to Golgi trafficking, which could be fully rescued upon Dymeclin re-expression. These findings indicate that Dymeclin is crucial for proper myelination and anterograde neuronal trafficking, two processes that are highly active during postnatal brain maturation.


Asunto(s)
Enanismo/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Microcefalia/genética , Osteocondrodisplasias/congénito , Proteínas/genética , Animales , Preescolar , Regulación hacia Abajo , Retículo Endoplásmico Rugoso/metabolismo , Femenino , Aparato de Golgi/metabolismo , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Mutantes , Mutación , Vaina de Mielina/genética , Vaina de Mielina/fisiología , Osteocondrodisplasias/genética , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología
20.
BMC Med Genet ; 18(1): 48, 2017 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-28464862

RESUMEN

BACKGROUND: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. CASE PRESENTATION: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. CONCLUSIONS: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly.


Asunto(s)
Complejo 4 de Proteína Adaptadora/genética , Microcefalia/genética , Mutación , Humanos , Recién Nacido , Masculino
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