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1.
Am J Hum Genet ; 108(6): 1126-1137, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-34010604

RESUMEN

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.


Asunto(s)
Enfermedades Óseas/etiología , Enfermedades Cardiovasculares/etiología , Enfermedades del Tejido Conjuntivo/etiología , Inmunidad Celular/inmunología , Mutación con Pérdida de Función , Pérdida de Heterocigocidad , beta Carioferinas/genética , Adolescente , Adulto , Animales , Enfermedades Óseas/patología , Enfermedades Cardiovasculares/patología , Niño , Enfermedades del Tejido Conjuntivo/patología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven , Pez Cebra , beta Carioferinas/metabolismo
2.
Am J Med Genet A ; : e63874, 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39315659

RESUMEN

Radial ray deficiency (RRD) may be isolated, without other congenital anomalies or co-occurring with other, non-RRD, congenital anomalies. The prevalence and the types of co-occurring anomalies are variable in the reported studies. The aim of this study was to obtain the prevalence and the types of co-occurring congenital anomalies among cases with RRD in a geographically well-characterized population of 387,067 consecutive births in northeastern France from 1979 to 2007 including live births, stillbirths and terminations of pregnancy. During the study period 83 cases with RRD were ascertained (prevalence of 2.14 per 10,000 births), 63 cases (75.9%) had co-occurring anomalies. Cases with co-occurring anomalies were divided into chromosomal anomalies (18 cases, 22%), syndromic conditions (syndromes and associations, 23 cases, 28%), and multiple congenital anomalies (MCA) (22 cases, 26%). Trisomies 18 and autosomal deletions were the most common chromosomal abnormalities. Thrombocytopenia absent radii syndrome, VACTERL association, Fanconi anemia, Roberts syndrome, and Holt-Oram syndrome were the most common syndromic conditions. Anomalies in the musculoskeletal, the cardiovascular, the urinary, and the orofacial system were the most common co-occurring anomalies in cases with MCA. As cases with RRD have often co-occurring congenital anomalies, a multidisciplinary checkup of these cases is recommended.

3.
J Med Genet ; 59(4): 377-384, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-33737400

RESUMEN

INTRODUCTION: This study aims to define the phenotypic and molecular spectrum of the two clinical forms of ß-galactosidase (ß-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB). METHODS: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed. RESULTS: The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group. CONCLUSION: This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.


Asunto(s)
Gangliosidosis GM1 , Mucopolisacaridosis IV , Femenino , Gangliósido G(M1) , Gangliosidosis GM1/genética , Humanos , Mucopolisacaridosis IV/genética , Mutación , Embarazo , beta-Galactosidasa/genética
4.
Genet Med ; 24(1): 179-191, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34906456

RESUMEN

PURPOSE: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. METHODS: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. RESULTS: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. CONCLUSION: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.


Asunto(s)
Discapacidad Intelectual , Trastornos del Desarrollo del Lenguaje , Anomalías Musculoesqueléticas , Haploinsuficiencia , Humanos , Discapacidad Intelectual/diagnóstico , Trastornos del Desarrollo del Lenguaje/genética , Anomalías Musculoesqueléticas/genética , Fenotipo
5.
Am J Med Genet A ; 188(6): 1700-1715, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35179301

RESUMEN

Oral clefts (OCs) are frequently co-occurring with other non-OC congenital anomalies. The types and the prevalence of anomalies co-occurring with OCs vary in the reported studies. The aims of this report were to study the types and the prevalence of the anomalies co-occurring with OCs in a well-defined population. The types and the prevalence of anomalies co-occurring in cases with OCs were ascertained in all terminations of pregnancy, stillbirths, and live births in 387,067 births occurring consecutively during the period 1979-2007 in the area covered by our registry of congenital anomalies which is population based, 789 cases of OCs were registered during the study period with a prevalence of 20.4 per 10,000 births, 39.5% of the cases had associated non-OC anomalies. Associated anomalies were more common in cases with cleft palate (52.4%) than in cases with cleft lip and palate (37.3%) and in cases with cleft lip only (16.8%). Chromosomal abnormalities were present in 94 (11.9%) cases including 27 trisomies 13, 15 trisomies 18, 12 22 q11.2 deletion, and 40 other chromosomal abnormalities. Nonchromosomal recognizable conditions were diagnosed in 38 cases (4.8%) including syndromes, associations, spectrums and sequences. Multiple congenital anomalies (MCAs) were present in 180 cases (22.8%). The most frequent MCA were in the musculoskeletal system (16.7%), the central nervous system (15.0%), the urogenital system (13.7%), the cardiovascular system (8.6%), and the digestive system (6.6%). The high prevalence of associated anomalies justifies a thorough screening for other congenital anomalies in cases with OCs.


Asunto(s)
Anomalías Múltiples , Labio Leporino , Fisura del Paladar , Cardiopatías Congénitas , Enfermedades Musculoesqueléticas , Anomalías Múltiples/epidemiología , Anomalías Múltiples/genética , Aberraciones Cromosómicas , Labio Leporino/complicaciones , Labio Leporino/epidemiología , Labio Leporino/genética , Fisura del Paladar/complicaciones , Fisura del Paladar/epidemiología , Fisura del Paladar/genética , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Humanos , Embarazo , Prevalencia , Trisomía
6.
Genet Med ; 23(1): 111-122, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32855533

RESUMEN

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.


Asunto(s)
Aneurisma de la Aorta Torácica , Disección Aórtica , Proteínas ADAM , Disección Aórtica/genética , Animales , Aneurisma de la Aorta Torácica/genética , Exoma/genética , Fibrilina-1/genética , Humanos , Ratones
7.
Am J Med Genet A ; 185(7): 1954-1971, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33881198

RESUMEN

The pathogenesis of omphalocele and gastroschisis is not obvious. Their etiology is disputed. The prevalence and the types of anomalies co-occurring with omphalocele and gastroschisis are variable in the different series published. The aim of this study was to estimate the frequency and the types of co-occurring anomalies in cases with gastroschisis and omphalocele. This study was performed in a well-described population of 387,067 consecutive births between 1979 and 2007. Hundred-one cases with omphalocele were registered (2.61 per 10,000), 75 (74.3%) had co-occurring anomalies comprising chromosomal anomalies (28 cases, 27.7%, including 18 trisomy 18), non-chromosomal syndromes (16 cases, 15.8%, including 3 cases with Beckwith-Wiedemann syndrome, 2 cases with the OEIS sequence, and one case with the Pentalogy of Cantrell complex), and 31 cases, 30.7% with MCA (multiple congenital anomalies). The most common MCA were musculoskeletal (23.5%), urogenital (20.4%), cardiovascular (15.1%), and central nervous (9.1%). Seventy-one cases of gastroschisis were ascertained (1.83 per 10,000). However, the prevalence increased during the study period. The frequency was highest in the mothers 15-19 years old. Sixteen out of the 71 cases with gastroschisis, (22.5%) had co-occurring anomalies including 11 cases of MCA and 5 cases with syndromes. To conclude, the frequency and the types of anomalies co-occurring with omphalocele and gastroschisis are peculiar. Therefore, cases with gastroschisis and omphalocele need to be screened for co-occurring anomalies.


Asunto(s)
Síndrome de Beckwith-Wiedemann/diagnóstico , Gastrosquisis/diagnóstico , Hernia Umbilical/diagnóstico , Síndrome de la Trisomía 18/genética , Pared Abdominal/patología , Adolescente , Adulto , Síndrome de Beckwith-Wiedemann/complicaciones , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patología , Aberraciones Cromosómicas , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/genética , Anomalías Congénitas/patología , Femenino , Gastrosquisis/complicaciones , Gastrosquisis/genética , Gastrosquisis/patología , Hernia Umbilical/complicaciones , Hernia Umbilical/genética , Hernia Umbilical/patología , Humanos , Recién Nacido , Edad Materna , Madres , Síndrome de la Trisomía 18/complicaciones , Síndrome de la Trisomía 18/diagnóstico , Síndrome de la Trisomía 18/patología , Adulto Joven
8.
J Med Genet ; 57(6): 389-399, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32015000

RESUMEN

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.


Asunto(s)
Proteínas de Ciclo Celular/genética , Enfermedades Cocleares/genética , Microcefalia/genética , Proteínas del Tejido Nervioso/genética , Niño , Preescolar , Cóclea/diagnóstico por imagen , Cóclea/metabolismo , Cóclea/patología , Enfermedades Cocleares/diagnóstico por imagen , Enfermedades Cocleares/patología , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Femenino , Humanos , Hipotálamo/diagnóstico por imagen , Hipotálamo/patología , Lactante , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/patología , Mutación , Neurogénesis/genética , Linaje , Retina/diagnóstico por imagen , Retina/patología
9.
Hum Mutat ; 41(7): 1220-1225, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32227665

RESUMEN

Thrombocytopenia-absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5'-untranslated region (5'-UTR) and 3'-UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.


Asunto(s)
Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Proteínas de Unión al ARN/genética , Trombocitopenia/genética , Deformidades Congénitas de las Extremidades Superiores/genética , Regiones no Traducidas 5' , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 1 , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Radio (Anatomía)/patología , Adulto Joven
10.
Genet Med ; 22(3): 524-537, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31578471

RESUMEN

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.


Asunto(s)
Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Factores de Transcripción SOXD/genética , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Haploinsuficiencia/genética , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Trastornos del Desarrollo del Lenguaje/diagnóstico , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/patología , Masculino , Mutación Missense/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/patología , Linaje , Fenotipo , Adulto Joven
11.
PLoS Genet ; 13(8): e1006957, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28859103

RESUMEN

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.


Asunto(s)
Regulación de la Expresión Génica/genética , Hipotálamo/fisiología , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Obesidad/genética , Factores de Transcripción/genética , Adulto , Animales , Sistemas CRISPR-Cas , Línea Celular , Niño , Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Femenino , Técnicas de Inactivación de Genes , Humanos , Hipotálamo/metabolismo , Hipotálamo/patología , Discapacidad Intelectual/fisiopatología , Masculino , Mutación , Obesidad/fisiopatología , Polimorfismo de Nucleótido Simple/genética , Pez Cebra
12.
Brain ; 141(11): 3160-3178, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30351409

RESUMEN

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.


Asunto(s)
Epilepsia Generalizada/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Mutación/genética , Canales de Potasio/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Anciano , Animales , Células CHO , Niño , Preescolar , Cricetulus , Estimulación Eléctrica , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Potenciales de la Membrana/genética , Persona de Mediana Edad , Modelos Moleculares , Mutagénesis Sitio-Dirigida/métodos , Adulto Joven
13.
Am J Med Genet A ; 176(12): 2646-2660, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30548801

RESUMEN

Anorectal anomalies (ARA) are common congenital anomalies. The etiology of ARA is unclear and its pathogenesis is controversial. Cases with ARA often have other non-ARA-associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with ARA were collected in all live births, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 202 cases with ARA, representing a prevalence of 5.21 per 10,000, 100 (49.5%) had associated anomalies. There were 7 (3.3%) cases with chromosomal abnormalities, and 31 (15.3%) nonchromosomal recognized dysmorphic conditions, including 17 cases with Vertebral defects, Anal atresia, Cardiac septal defects, esophageal atresia or TracheoEsophageal fistula, Renal anomalies and radial Limb defects association. Sixty two (30.7%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the urogenital, the musculoskeletal, the cardiovascular, the digestive, and the central nervous systems were the most common other anomalies in the cases with MCA. The anomalies associated with ARA could be classified into a recognizable malformation syndrome or pattern in 38 out of the 100 cases (38%) with associated anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion, the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a routine screening for other anomalies in cases with ARA.


Asunto(s)
Anomalías Múltiples/epidemiología , Anomalías Múltiples/etiología , Malformaciones Anorrectales/epidemiología , Malformaciones Anorrectales/etiología , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/cirugía , Malformaciones Anorrectales/diagnóstico , Malformaciones Anorrectales/cirugía , Preescolar , Aberraciones Cromosómicas , Femenino , Humanos , Lactante , Recién Nacido , Nacimiento Vivo , Masculino , Oportunidad Relativa , Fenotipo , Vigilancia de la Población , Prevalencia , Sistema de Registros , Mortinato
14.
Hum Mol Genet ; 24(11): 3038-49, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25669657

RESUMEN

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder.


Asunto(s)
Amelogénesis Imperfecta/genética , Proteínas de Unión a TGF-beta Latente/genética , Osteocondrodisplasias/genética , Adolescente , Amelogénesis Imperfecta/diagnóstico por imagen , Animales , Secuencia de Bases , Niño , Consanguinidad , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Estudios de Asociación Genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación Missense , Osteocondrodisplasias/diagnóstico por imagen , Linaje , Radiografía , Eliminación de Secuencia
15.
Am J Med Genet A ; 173(8): 2139-2157, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28577344

RESUMEN

Esophageal atresia (EA) is a common type of congenital anomaly. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Infants with esophageal atresia often have other non-EA associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with EA were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 116 cases with esophageal atresia, representing a prevalence of 2.99 per 10,000, 54 (46.6%) had associated anomalies. There were 9 (7.8%) cases with chromosomal abnormalities including 6 trisomies 18, and 20 (17.2%) nonchromosomal recognized dysmorphic conditions including 12 cases with VACTERL association and 2 cases with CHARGE syndrome. Twenty five (21.6%) of the cases had multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the digestive, the urogenital, the musculoskeletal, and the central nervous systems were the most common other anomalies. The anomalies associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 29 out of 54 cases (53.7%). This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA.


Asunto(s)
Trastornos de los Cromosomas/fisiopatología , Anomalías Congénitas/fisiopatología , Atresia Esofágica/fisiopatología , Anomalías Múltiples/epidemiología , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Canal Anal/anomalías , Canal Anal/fisiopatología , Aberraciones Cromosómicas , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/epidemiología , Trastornos de los Cromosomas/genética , Anomalías Congénitas/epidemiología , Anomalías Congénitas/genética , Atresia Esofágica/complicaciones , Atresia Esofágica/epidemiología , Atresia Esofágica/genética , Esófago/anomalías , Esófago/fisiopatología , Femenino , Feto/fisiopatología , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/fisiopatología , Humanos , Riñón/anomalías , Riñón/fisiopatología , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/epidemiología , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/fisiopatología , Masculino , Embarazo , Columna Vertebral/anomalías , Columna Vertebral/fisiopatología , Mortinato , Tráquea/anomalías , Tráquea/fisiopatología
16.
Nature ; 478(7367): 97-102, 2011 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-21881559

RESUMEN

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.


Asunto(s)
Índice de Masa Corporal , Cromosomas Humanos Par 16/genética , Dosificación de Gen/genética , Obesidad/genética , Fenotipo , Delgadez/genética , Adolescente , Adulto , Anciano , Envejecimiento , Estatura/genética , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Metabolismo Energético/genética , Europa (Continente) , Femenino , Duplicación de Gen/genética , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Cabeza/anatomía & histología , Heterocigoto , Humanos , Lactante , Recién Nacido , Masculino , Trastornos Mentales/genética , Persona de Mediana Edad , Mutación/genética , América del Norte , ARN Mensajero/análisis , ARN Mensajero/genética , Eliminación de Secuencia/genética , Transcripción Genética , Adulto Joven
17.
J Med Genet ; 53(2): 98-110, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26502894

RESUMEN

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Anomalías Dentarias/genética , Amelogénesis Imperfecta/genética , Autoantígenos/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 11/genética , Estudios de Cohortes , Coloboma/genética , Displasia de la Dentina/genética , Francia , Pérdida Auditiva Sensorineural/genética , Humanos , Colágenos no Fibrilares/genética , Reproducibilidad de los Resultados , Colágeno Tipo XVII
18.
Am J Med Genet A ; 167A(5): 1008-17, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25728055

RESUMEN

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.


Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Estudios de Asociación Genética , Discapacidad Intelectual/genética , Anomalías Múltiples/clasificación , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Anciano , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Discapacidad Intelectual/clasificación , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo
19.
J Med Genet ; 51(11): 724-36, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25167861

RESUMEN

BACKGROUND: Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. METHODS: We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. RESULTS: We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. CONCLUSIONS: With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Técnicas de Diagnóstico Molecular/métodos , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Análisis de Secuencia de ADN/métodos , Adulto Joven
20.
Eur J Med Genet ; 67: 104892, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38110175

RESUMEN

Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these associated anomalies vary between different studies. The purpose of this investigation was to assess the frequency and the types of associated anomalies among cases with an/microphthalmia in a geographically well defined population of northeastern France of 387,067 consecutive pregnancies from 1979 to 2007. Of the 98 infants with an/microphthalmia born during this period (prevalence at birth of 2.53 per 10,000), 88.8 % had associated anomalies. Cases with associated anomalies were divided into recognizable conditions (25 (25.5%) cases with chromosomal and 17 (17.3%) cases with non chromosomal conditions), and non recognizable conditions (45-45.9%- cases with multiple congenital anomalies -MCA). Trisomy 13 and trisomy 18 were the most frequent chromosomal abnormalities. Amniotic bands sequence, oculo-auriculo-vertebral spectrum, CHARGE syndrome and VACTERL association were most often present in recognizable non chromosomal conditions. Anomalies in the musculoskeletal, cardiovascular and central nervous systems were the most common other anomalies in cases with MCA and non recognizable conditions. However, given the limitation of the limited numbers of cases there should be urging caution in interpreting these results. In conclusion the frequency of associated anomalies in infants with anophthalmia and microphthalmia emphasizes the need for a thorough investigation of these cases. Routine screening for other anomalies especially musculoskeletal, cardiac and central nervous systems anomalies may need to be considered in infants with anophthalmia and microphthalmia, and referral of these cases for genetic counselling seems warranty.


Asunto(s)
Anoftalmos , Síndrome CHARGE , Cardiopatías Congénitas , Deformidades Congénitas de las Extremidades , Microftalmía , Lactante , Recién Nacido , Embarazo , Femenino , Humanos , Anoftalmos/epidemiología , Anoftalmos/genética , Microftalmía/epidemiología , Microftalmía/genética , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Prevalencia
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