Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Hum Genet ; 143(6): 761-773, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38787418

RESUMEN

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.


Asunto(s)
Metilación de ADN , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Masculino , Femenino , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Niño
2.
Am J Hum Genet ; 106(3): 405-411, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32109420

RESUMEN

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.


Asunto(s)
Mutación Missense , Trastornos del Neurodesarrollo/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Adolescente , Niño , Preescolar , Facies , Femenino , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Cráneo/anomalías , Adulto Joven
3.
Hum Mutat ; 43(12): 1844-1851, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35904126

RESUMEN

TATA-binding protein associated factor 4 (TAF4) is a subunit of the Transcription Factor IID (TFIID) complex, a central player in transcription initiation. Other members of this multimeric complex have been implicated previously as monogenic disease genes in human developmental disorders. TAF4 has not been described to date as a monogenic disease gene. We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD). Common features include intellectual disability, abnormal behavior, and facial dysmorphisms. We propose TAF4 as a novel dominant disease gene for NDD, and coin this novel disorder "TAF4-related NDD" (T4NDD). We place T4NDD in the context of other disorders related to TFIID subunits, revealing shared features of T4NDD with other TAF-opathies.


Asunto(s)
Trastornos del Neurodesarrollo , Factores Asociados con la Proteína de Unión a TATA , Factor de Transcripción TFIID , Niño , Humanos , Discapacidades del Desarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Factores Asociados con la Proteína de Unión a TATA/genética , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factor de Transcripción TFIID/genética , Factor de Transcripción TFIID/metabolismo
4.
Hum Mol Genet ; 29(9): 1426-1439, 2020 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-32202298

RESUMEN

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.


Asunto(s)
Acetiltransferasas/genética , Flavoproteínas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedades del Sistema Nervioso/genética , Proteínas Nucleares/genética , Monoéster Fosfórico Hidrolasas/genética , Factores de Transcripción/genética , Acetiltransferasas/química , Acetiltransferasas/ultraestructura , Edad de Inicio , Antígenos de Superficie/genética , Núcleo Celular/genética , Niño , Preescolar , Exodesoxirribonucleasas/genética , Femenino , Regulación de la Expresión Génica/genética , Glicoproteínas/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Péptidos y Proteínas de Señalización Intracelular/química , Intrones/genética , Masculino , Enfermedades del Sistema Nervioso/patología , Proteínas Nucleares/ultraestructura , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Fenotipo , Fosfoproteínas/genética , Conformación Proteica , Transporte de ARN/genética , ARN Mensajero/genética
5.
Clin Genet ; 98(1): 91-98, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32335897

RESUMEN

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.


Asunto(s)
Ribonucleoproteínas Nucleares Heterogéneas/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Adulto , Niño , Preescolar , Epilepsia/genética , Femenino , Genes Ligados a X/genética , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Síndrome , Adulto Joven
6.
Am J Hum Genet ; 97(4): 621-6, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26387593

RESUMEN

Tooth agenesis is one of the most common developmental anomalies in man. Oligodontia, a severe form of tooth agenesis, occurs both as an isolated anomaly and as a syndromal feature. We performed exome sequencing on 20 unrelated individuals with apparent non-syndromic oligodontia and failed to detect mutations in genes previously associated with oligodontia. In three of the probands, we detected heterozygous variants in LRP6, and sequencing of additional oligodontia-affected individuals yielded one additional mutation in LRP6. Three mutations (c.1144_1145dupAG [p.Ala383Glyfs(∗)8], c.1779dupT [p.Glu594(∗)], and c.2224_2225dupTT [p.Leu742Phefs(∗)7]) are predicted to truncate the protein, whereas the fourth (c.56C>T [p.Ala19Val]) is a missense variant of a conserved residue located at the cleavage site of the protein's signal peptide. All four affected individuals harboring a LRP6 mutation had a family history of tooth agenesis. LRP6 encodes a transmembrane cell-surface protein that functions as a co-receptor with members from the Frizzled protein family in the canonical Wnt/ß-catenin signaling cascade. In this same pathway, WNT10A was recently identified as a major contributor in the etiology of non-syndromic oligodontia. We show that the LRP6 missense variant (c.56C>T) results in altered glycosylation and improper subcellular localization of the protein, resulting in abrogated activation of the Wnt pathway. Our results identify LRP6 variants as contributing to the etiology of non-syndromic autosomal-dominant oligodontia and suggest that this gene is a candidate for screening in DNA diagnostics.


Asunto(s)
Anodoncia/genética , Exoma/genética , Genes Dominantes , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Mutación/genética , Proteínas Wnt/genética , Anodoncia/patología , Estudios de Casos y Controles , Femenino , Células HEK293 , Humanos , Masculino , Linaje , Fenotipo
7.
Am J Med Genet A ; 176(6): 1349-1368, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29696787

RESUMEN

The triad of micrognathia, glossoptosis, and concomitant airway obstruction defined as "Robin sequence" (RS) is caused by oropharyngeal developmental events constrained by a reduced stomadeal space. This sequence of abnormal embryonic development also results in an anatomical configuration that might predispose the fetus to a cleft palate. RS is heterogeneous and many different etiologies have been described including syndromic, RS-plus, and isolated forms. For an optimal diagnosis, subsequent treatment and prognosis, a thorough understanding of the embryology and pathogenesis is necessary. This manuscript provides an update about our current understanding of the development of the mandible, tongue, and palate and possible mechanisms involved in the development of RS. Additionally, we provide the reader with an up-to-date summary of the different etiologies of this phenotype and link this to the embryologic, developmental, and genetic mechanisms.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Mandíbula/embriología , Hueso Paladar/embriología , Síndrome de Pierre Robin/etiología , Lengua/embriología , Femenino , Humanos , Síndrome de Pierre Robin/fisiopatología , Embarazo
8.
Brain ; 140(8): 2093-2103, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28633435

RESUMEN

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.


Asunto(s)
Acetiltransferasas/genética , Enfermedad de Charcot-Marie-Tooth/genética , Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Acetiltransferasas/metabolismo , Adolescente , Adulto , Células Cultivadas , Enfermedad de Charcot-Marie-Tooth/complicaciones , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Humanos , Discapacidad Intelectual/complicaciones , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Mutación , Linaje , Adulto Joven
9.
Eur J Pediatr ; 177(5): 781-789, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29492661

RESUMEN

Although Robin sequence (RS) is a well-known phenomenon, it is still associated with considerable morbidity and even mortality. The purposes of this study were to gain greater insight into the mortality rate and identify risk factors associated with mortality in RS. We retrospectively reviewed all RS infants followed at the Wilhelmina Children's Hospital from 1995 to 2016. Outcome measurements were death and causes of death. The authors identified 103 consecutive RS infants with a median follow-up of 8.6 years (range 0.1-21.9 years). Ten of the 103 infants (10%) died at a median age of 0.8 years (range 0.1-5.9 years). Nine of these ten infants (90%) were diagnosed with an associated syndrome. Of these, seven infants died of respiratory insufficiency due to various causes (two related to upper airway obstruction). The other two syndromic RS infants died of arrhythmia due to hypernatremia and of West syndrome with status epilepticus. One isolated RS infant died of brain ischemia after MDO surgery. Cardiac anomalies were observed in 41% and neurological anomalies in 36%. The presence of a neurological anomaly was associated with a mortality rate of 40% versus 7% in infants with no neurological anomaly (p = 0.016), with an odds ratio of 8.3 (95% CI 1.4-49.0) for neurological anomaly versus no neurological anomaly. Mortality was 15% in infants with syndromic RS versus 2% in infants with isolated RS (p = 0.044). Mortality was not significantly associated with the presence of a cardiac anomaly, surgical treatment for severe respiratory distress in the neonatal period, or prematurity. CONCLUSION: RS represents a heterogeneous patient population and is associated with a high level of underlying syndromes. The present study reports a mortality rate of 10% significantly associated with syndromic RS and the presence of neurological anomalies. A multidisciplinary approach in all infants born with RS, including genetic testing and examination of neurological anomalies in a standardized way, is crucial to identify infants with underlying syndromes potentially associated with increased mortality. What is Known: • Reported mortality rates in Robin sequence vary from 2% to 26%. • Clinicians mainly focus on the morbidity of Robin sequence that includes respiratory complications due to upper airway obstruction in the period after birth. • Robin sequence represents a heterogeneous patient population and is associated with a high level of underlying syndromes. What is New: • The present study reports a mortality rate of 10% significantly associated with syndromic Robin sequence and the presence of neurological anomalies. • A multidisciplinary approach in all infants born with Robin sequence, including genetic evaluation and standardized workup for neurological anomalies, is crucial to identify infants with underlying syndromes potentially associated with increased mortality.


Asunto(s)
Síndrome de Pierre Robin/mortalidad , Causas de Muerte , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Síndrome de Pierre Robin/complicaciones , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo
10.
J Craniofac Surg ; 29(4): 985-987, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29485558

RESUMEN

OBJECTIVE: Heterogeneity in both nomenclature and diagnostic criteria has hindered the interpretation of research into the congenital condition most widely known as (Pierre) Robin syndrome or sequence. In 2009, the discussion regarding its diagnosis and nosology was reopened to converge on a uniform eponym and standard set of diagnostic criteria. The objective of this study was to assess the impact of this debate. MATERIALS AND METHODS: This is a retrospective review of the nomenclature and diagnostic criteria employed in studies about this condition that were indexed in the MEDLINE literature database (PubMed) and published during 2009 to 2016. RESULTS: A total of 440 studies were retrieved of which the majority used the eponyms "Pierre Robin sequence" (62.0%) or "Robin sequence" (23.4%). During the study period, there was a significant shift toward the use of "sequence" in preference over "syndrome." Only 71.4% of studies mentioned their criteria for diagnosis, which remained heterogeneous throughout the study period. CONCLUSION: Since 2009, the debate has not produced a consensus eponym and standard diagnosis. This is unfortunate given the enduring controversies over the optimal management of a condition associated with a high morbidity and mortality. A renewed effort is needed to arrive at a workable consensus to enhance the retrievability of relevant literature and facilitate the interpretation of outcome studies.


Asunto(s)
Síndrome de Pierre Robin , Consenso , Humanos , Síndrome de Pierre Robin/clasificación , Síndrome de Pierre Robin/diagnóstico , Estudios Retrospectivos , Terminología como Asunto
11.
Prenat Diagn ; 37(2): 162-167, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27943390

RESUMEN

OBJECTIVES: Polyhydramnios is suggested to be associated with oral clefts (OCs) due to swallowing problems. This study assessed incidence and outcome of idiopathic polyhydramnios in isolated OC pregnancies. METHODS: This was a retrospective cohort study of prenatally diagnosed OC. The incidence of idiopathic polyhydramnios in isolated OC pregnancies was determined. Pregnancy outcome, neonatal and paediatric follow-up were compared between cases with polyhydramnios and those with normal amniotic fluid. Subgroup analysis was conducted to evaluate whether an association exists between polyhydramnios and presence of associated anomalies diagnosed after birth. RESULTS: In 230 cases of isolated OC, 15 developed polyhydramnios (6.5%). Involvement of the palate was significantly more common in the presence than in the absence of polyhydramnios (13/15 or 87% vs 125/215 or 58%, p = 0.03, odds ratio 4.7, 95% confidence interval 1.0-30.8). No significant differences were seen in pregnancy outcome or neonatal and paediatric follow-up between the two groups. In subgroup analysis, rate of polyhydramnios was not significantly different in associated cases that appeared isolated prenatally (1/27; 3.7%) compared with that in the isolated cases (15/230; 6.5%). CONCLUSIONS: The incidence of idiopathic polyhydramnios in isolated OC pregnancies is 6.5%. Polyhydramnios in isolated OC increases the risk of palate involvement. The presence of polyhydramnios is not associated with adverse perinatal or long-term outcome. If isolated at prenatal assessment, polyhydramnios does not increase the risk of associated anomalies postpartum. © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Labio Leporino/epidemiología , Fisura del Paladar/epidemiología , Polihidramnios/epidemiología , Resultado del Embarazo/epidemiología , Adolescente , Adulto , Labio Leporino/complicaciones , Labio Leporino/diagnóstico , Fisura del Paladar/complicaciones , Fisura del Paladar/diagnóstico , Femenino , Humanos , Incidencia , Polihidramnios/diagnóstico , Polihidramnios/etiología , Embarazo , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Diagnóstico Prenatal/estadística & datos numéricos , Estudios Retrospectivos , Adulto Joven
12.
Hum Genet ; 134(1): 97-109, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25326669

RESUMEN

Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.


Asunto(s)
Discapacidad Intelectual/genética , Microcefalia/genética , Mutación/genética , beta Catenina/genética , Niño , Preescolar , Femenino , Estudios de Seguimiento , Haploinsuficiencia , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Microcefalia/patología , Fenotipo , Síndrome
13.
Am J Med Genet A ; 167A(9): 1972-82, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25994858

RESUMEN

The birth prevalence of Robin sequence (RS) is frequently cited to be 1 in 8,500 to 14,000 live births (range: 7,1-11,8 per 100.000), which is based on just a few epidemiological studies. The objective of this study is to contribute to the limited knowledge of the epidemiology of RS by determining the frequency of RS in a cleft palate (CP) population and the estimated birth prevalence in live births in the Netherlands, using distinct diagnostic criteria. A retrospective population-based analysis of the National Cleft Registry was performed in order to obtain all CP patients registered in the Netherlands from 2000-2010, in addition to a thorough review of the medical records in three Dutch Academic Pediatric Hospitals for the same period. Furthermore, a systematic search of the literature was conducted to allow for comparison of our findings. The Dutch birth prevalence of RS was estimated to be 1:5,600 live births (or 17.7 per 100,000), with a slight female predominance. RS was estimated to occur in a third of the CP population and patients with RS had a more severe cleft grade than the general CP population. The literature search yielded 42 studies reporting the birth prevalence for RS, which varied between 1:3,900 and 1:122,400 (0.8-32.0 per 100,000), with a mean prevalence of 1:24,500 (8.0 per 100,000). The birth prevalence of RS in the Netherlands was higher than reported for most other countries when similar diagnostic criteria were used, with a slight female predominance. A third of the general CP could be classified as RS.


Asunto(s)
Síndrome de Pierre Robin/epidemiología , Labio Leporino/epidemiología , Fisura del Paladar/epidemiología , Femenino , Humanos , Nacimiento Vivo/epidemiología , Masculino , Países Bajos/epidemiología , Prevalencia , Estudios Retrospectivos
14.
Am J Med Genet A ; 167A(9): 1983-92, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26033782

RESUMEN

Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated.


Asunto(s)
Síndrome de Pierre Robin/etiología , Síndrome de Pierre Robin/patología , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/patología , Artritis/etiología , Artritis/patología , Fisura del Paladar/patología , Enfermedades del Tejido Conjuntivo/etiología , Enfermedades del Tejido Conjuntivo/patología , Femenino , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Micrognatismo/etiología , Micrognatismo/patología , Desprendimiento de Retina/etiología , Desprendimiento de Retina/patología
15.
Sci Transl Med ; 15(698): eabo3189, 2023 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-37256937

RESUMEN

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.


Asunto(s)
Interferón Tipo I , Complejo de la Endopetidasa Proteasomal , Animales , Humanos , Ratones , Adenosina Trifosfatasas/genética , Drosophila melanogaster , Expresión Génica , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteómica
16.
Eur J Paediatr Neurol ; 41: 91-98, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36410285

RESUMEN

Vici syndrome (OMIM 242840) is a very rare autosomal recessive multisystem disorder first described in 1988. In 2013, bi-allelic loss-of-function mutations in EPG5 were reported to cause Vici syndrome. Five principal diagnostic features of Vici syndrome have been proposed: agenesis of the corpus callosum, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. We identified 15 patients carrying a homozygous founder missense variant in EPG5 who all exhibit a less severe clinical phenotype than classic Vici syndrome. All 15 show typical brain abnormalities on MRI. The homozygous founder variant in EPG5 they carry results in a shorter in-frame transcript and truncated, but likely still residual, EPG5 protein. We speculate that the residual EPG5 protein explains their attenuated phenotype, which is consistent with two previous observations that low expression of EPG5 can lead to an attenuated Vici syndrome phenotype. We propose renaming this condition EPG5-related neurodevelopmental disorder to emphasize the clinical variability of patients with bi-allelic mutations in EPG5.


Asunto(s)
Catarata , Humanos , Catarata/genética , Fenotipo , Homocigoto , Cuerpo Calloso , Proteínas Relacionadas con la Autofagia , Proteínas de Transporte Vesicular/genética
17.
Hum Mutat ; 32(2): E2018-25, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21280141

RESUMEN

Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS.


Asunto(s)
Proteínas de Unión al ADN/genética , Mutación , Proteínas de Neoplasias/genética , Anomalías Múltiples/genética , Cara/anomalías , Femenino , Enfermedades Hematológicas/genética , Humanos , Masculino , Enfermedades Vestibulares/genética
18.
Front Pediatr ; 9: 651995, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34277514

RESUMEN

Objective: Developmental language delay (DLD) is one of the most common disabilities in childhood and can negatively affect a child's communication skills and academic and/or psychosocial development. To date, an increasing number of causative genes have been identified by diagnostic techniques like next generation sequencing. An early genetic diagnosis is important to properly prepare and counsel children and parents for possible future difficulties. Despite this, genetic assessment is usually not part of a standardized diagnostic set in children with developmental language delay. In this study, we aim to assess the diagnostic outcomes of children primarily assessed for speech and language delay who were subsequently referred for genetic etiological assessment. Methods: Medical records of children referred to the department of Otorhinolaryngology of the Wilhelmina Children's Hospital for diagnostic work-up for a suspected speech and language delay between June 2011 and December 2018 who were additionally referred to a geneticist were evaluated. Study parameters concerning medical history, behavioral problems, language development, intelligence, and hearing were recorded. Outcomes of genetic analysis were evaluated. Results: A total of 127 patients were diagnosed with a developmental language delay. Genetic analysis was conducted in 119 out of 127 patients with a language delay and eligible for this study. The median time between initial speech and language assessment and the first genetic consultation was 10 months (IQR 5.0-23.0). In 34 out of 127 patients a causative genetic diagnosis was found to explain their DLD. Conclusion: In approximately a quarter of the patients (26.8%) diagnosed with developmental language delay, a causative genetic diagnosis was confirmed. This demonstrates the opportunity to identify an underlying genetic etiology in children with developmental language delay. However, in order to optimize the diagnostic process and clinical care for these children, two important research gaps need to be addressed. First, research should focus on assessing the clinical impact and effect on treatment outcomes of a genetic diagnosis. Secondly, it is important to recognize for which children genetic testing is most beneficial.

19.
J Clin Med ; 10(21)2021 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-34768332

RESUMEN

Significant treatment variation exists in the Netherlands between teams treating patients with cleft lip, alveolus, and/or palate, resulting in a confusing and undesirable situation for patients, parents, and practitioners. Therefore, to optimize cleft care, clinical practice guidelines (CPGs) were developed. The aim of this report is to describe CPG development, share the main recommendations, and indicate knowledge gaps regarding cleft care. Together with patients and parents, a multidisciplinary working group of representatives from all relevant disciplines assisted by two experienced epidemiologists identified the topics to be addressed in the CPGs. Searching the Medline, Embase, and Cochrane Library databases identified 5157 articles, 60 of which remained after applying inclusion and exclusion criteria. We rated the quality of the evidence from moderate to very low. The working group formulated 71 recommendations regarding genetic testing, feeding, lip and palate closure, hearing, hypernasality, bone grafting, orthodontics, psychosocial guidance, dentistry, osteotomy versus distraction, and rhinoplasty. The final CPGs were obtained after review by all stakeholders and allow cleft teams to base their treatment on current knowledge. With high-quality evidence lacking, the need for additional high-quality studies has become apparent.

20.
Eur J Hum Genet ; 27(7): 1101-1112, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30850703

RESUMEN

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.


Asunto(s)
Alelos , Secuencia de Bases , Labio Leporino/genética , Fisura del Paladar/genética , Mutación con Pérdida de Función , Eliminación de Secuencia , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Adulto , Sustitución de Aminoácidos , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA