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MPDZ, a gene with diverse functions mediating cell-cell junction interactions, receptor signaling, and binding multivalent scaffold proteins, is associated with a spectrum of clinically heterogeneous phenotypes with biallelic perturbation. Despite its clinical relevance, the mechanistic underpinnings of these variants remain elusive, underscoring the need for extensive case series and functional investigations. In this study, we conducted a systematic review of cases in the literature through two electronic databases following the PRISMA guidelines. We selected nine studies, including 18 patients, with homozygous or compound heterozygous variants in MPDZ and added five patients from four unrelated families with novel MPDZ variants. To evaluate the role of Mpdz on hearing, we analyzed available auditory electrophysiology data from a knockout murine model (Mpdzem1(IMPC)J/em1(IMPC)J) generated by the International Mouse Phenotyping Consortium. Using exome and genome sequencing, we identified three families with compound heterozygous variants, and one family with a homozygous frameshift variant. MPDZ-related disease is clinically heterogenous with hydrocephaly, vision impairment, hearing impairment and cardiovascular disease occurring most frequently. Additionally, we describe two unrelated patients with spasticity, expanding the phenotypic spectrum. Our murine analysis of the Mpdzem1(IMPC)J/em1(IMPC)J allele showed severe hearing impairment. Overall, we expand understanding of MPDZ-related phenotypes and highlight hearing impairment and spasticity among the heterogeneous phenotypes.
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The prevalence of comorbidities in individuals with neurodevelopmental disorders (NDDs) is not well understood, yet these are important for accurate diagnosis and prognosis in routine care and for characterizing the clinical spectrum of NDD syndromes. We thus developed PhenomAD-NDD, an aggregated database containing the comorbid phenotypic data of 51,227 individuals with NDD, all harmonized into Human Phenotype Ontology (HPO), with in total 3,054 unique HPO terms. We demonstrate that almost all congenital anomalies are more prevalent in the NDD population than in the general population, and the NDD baseline prevalence allows for an approximation of the enrichment of symptoms. For example, such analyses of 33 genetic NDDs show that 32% of enriched phenotypes are currently not reported in the clinical synopsis in the Online Mendelian Inheritance in Man (OMIM). PhenomAD-NDD is open to all via a visualization online tool and allows us to determine the enrichment of symptoms in NDD.
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Comorbilidad , Trastornos del Neurodesarrollo , Fenómica , Fenotipo , Humanos , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/epidemiología , Prevalencia , Niño , Masculino , Femenino , Adolescente , PreescolarRESUMEN
Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype-phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.
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Inteligencia Artificial , Proteínas de Unión a la Región de Fijación a la Matriz , Humanos , Fenotipo , Algoritmos , Aprendizaje Automático , Variación Biológica Poblacional , Proteínas de Unión al ADN , Factores de TranscripciónRESUMEN
We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.
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Transducción de Señal , Pez Cebra , Animales , Humanos , Proteínas Serina-Treonina Quinasas , Péptidos y Proteínas de Señalización IntracelularRESUMEN
PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.
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Braquidactilia , Enanismo , Discapacidad Intelectual , Anomalías Musculoesqueléticas , Trastornos del Neurodesarrollo , Humanos , Trastornos del Neurodesarrollo/genética , Discapacidad Intelectual/genética , Enanismo/genética , Obesidad/genética , Fenotipo , Proteína-Arginina N-Metiltransferasas/genéticaRESUMEN
PURPOSE: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. METHODS: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. RESULTS: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. CONCLUSION: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Fosfoproteínas , Factores de Transcripción , Regulación de la Expresión Génica , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Fosfoproteínas/genética , Factores de Transcripción/genéticaRESUMEN
PURPOSE: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. METHODS: Clinical data was collected through an extensive web-based survey. RESULTS: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). CONCLUSION: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.
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Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Anomalías Múltiples , Proteínas Cromosómicas no Histona/genética , Cara/anomalías , Estudios de Asociación Genética , Deformidades Congénitas de la Mano/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Micrognatismo/genética , Cuello/anomalías , FenotipoRESUMEN
Recurrence risk calculations in autosomal recessive diseases are complicated when the effect of genetic variants and their population frequencies and penetrances are unknown. An example of this is Stargardt disease (STGD1), a frequent recessive retinal disease caused by bi-allelic pathogenic variants in ABCA4. In this cross-sectional study, 1,619 ABCA4 variants from 5,579 individuals with STGD1 were collected and categorized by (1) severity based on statistical comparisons of their frequencies in STGD1-affected individuals versus the general population, (2) their observed versus expected homozygous occurrence in STGD1-affected individuals, (3) their occurrence in combination with established mild alleles in STGD1-affected individuals, and (4) previous functional and clinical studies. We used the sum allele frequencies of these severity categories to estimate recurrence risks for offspring of STGD1-affected individuals and carriers of pathogenic ABCA4 variants. The risk for offspring of an STGD1-affected individual with the "severe|severe" genotype or a "severe|mild with complete penetrance" genotype to develop STGD1 at some moment in life was estimated at 2.8%-3.1% (1 in 36-32 individuals) and 1.6%-1.8% (1 in 62-57 individuals), respectively. The risk to develop STGD1 in childhood was estimated to be 2- to 4-fold lower: 0.68%-0.79% (1 in 148-126) and 0.34%-0.39% (1 in 296-252), respectively. In conclusion, we established personalized recurrence risk calculations for STGD1-affected individuals with different combinations of variants. We thus propose an expanded genotype-based personalized counseling to appreciate the variable recurrence risks for STGD1-affected individuals. This represents a conceptual breakthrough because risk calculations for STGD1 may be exemplary for many other inherited diseases.
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Transportadoras de Casetes de Unión a ATP , Asesoramiento Genético , Transportadoras de Casetes de Unión a ATP/genética , Estudios Transversales , Humanos , Mutación , Enfermedad de Stargardt/genéticaRESUMEN
PURPOSE: Although the introduction of exome sequencing (ES) has led to the diagnosis of a significant portion of patients with neurodevelopmental disorders (NDDs), the diagnostic yield in actual clinical practice has remained stable at approximately 30%. We hypothesized that improving the selection of patients to test on the basis of their phenotypic presentation will increase diagnostic yield and therefore reduce unnecessary genetic testing. METHODS: We tested 4 machine learning methods and developed PredWES from these: a statistical model predicting the probability of a positive ES result solely on the basis of the phenotype of the patient. RESULTS: We first trained the tool on 1663 patients with NDDs and subsequently showed that diagnostic ES on the top 10% of patients with the highest probability of a positive ES result would provide a diagnostic yield of 56%, leading to a notable 114% increase. Inspection of our model revealed that for patients with NDDs, comorbid abnormal (lower) muscle tone and microcephaly positively correlated with a conclusive ES diagnosis, whereas autism was negatively associated with a molecular diagnosis. CONCLUSION: In conclusion, PredWES allows prioritizing patients with NDDs eligible for diagnostic ES on the basis of their phenotypic presentation to increase the diagnostic yield, making a more efficient use of health care resources.
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Exoma , Trastornos del Neurodesarrollo , Exoma/genética , Humanos , Aprendizaje Automático , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Secuenciación del ExomaRESUMEN
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.
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Proteínas de Unión al ADN , Discapacidad Intelectual , Antígenos de Histocompatibilidad Menor , Proteínas de Unión al ADN/genética , Humanos , Discapacidad Intelectual/genética , Antígenos de Histocompatibilidad Menor/genética , Mutación Missense , Fenotipo , SíndromeRESUMEN
The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X-linked patterns of disease inheritance, such as ARX. In vitro functional analysis demonstrates that the transcriptional activity of all three variants was diminished compared to ARX-Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX-related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.
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Epilepsia/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Adolescente , Secuencia de Aminoácidos , Trastorno del Espectro Autista/genética , Preescolar , Secuencia Conservada , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación Missense , Linaje , Fenotipo , Dominios Proteicos , Adulto JovenRESUMEN
By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
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Anomalías Craneofaciales/genética , Discapacidades del Desarrollo/genética , Enanismo/genética , Variación Genética , Discapacidad Intelectual/genética , Histona Demetilasas con Dominio de Jumonji/genética , Anomalías Musculoesqueléticas/genética , Estatura , Niño , Exoma , Cara , Femenino , Estudios de Asociación Genética , Mutación de Línea Germinal , Haploinsuficiencia , Histonas/química , Humanos , Masculino , Mutación Missense , FenotipoRESUMEN
Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging from 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.
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Genes Dominantes , Enfermedades Genéticas Congénitas/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Pruebas Genéticas/estadística & datos numéricos , Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad/genética , Voluntarios Sanos , Heterocigoto , Humanos , Países Bajos , Secuenciación del Exoma/estadística & datos numéricosRESUMEN
BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.
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Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Masculino , Mutación , Trastornos del Neurodesarrollo/complicaciones , Síndrome , Adulto JovenRESUMEN
ABSTRACT: We report an unusual case of an adult patient carrying a germline PHOX2B frameshift mutation and hence was diagnosed with congenital central hypoventilation syndrome. He came to medical attention after the mutation was identified in his daughter who presented with hypoventilation and a neuroblastoma. Although PHOX2B mutations are usually associated with a phenotype of congenital hypoventilation, severe autonomic dysfunction and neural crest tumors, our patient had no complaints at the time of presentation. At polysomnography we found severe positional hypercapnic central sleep apnea, partly responsive to positional therapy. Eventually, he was titrated to noninvasive ventilation with resolution of the central breathing events and, in hindsight, a more refreshing sleep than before. Clinicians working in sleep medicine need to be aware of the variable expression of this rare condition to prevent late cardiorespiratory and neurocognitive complications.
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Proteínas de Homeodominio/genética , Hipoventilación/congénito , Mutación/genética , Apnea Central del Sueño/complicaciones , Apnea Central del Sueño/fisiopatología , Factores de Transcripción/genética , Adulto , Humanos , Hipoventilación/complicaciones , Hipoventilación/genética , Hipoventilación/fisiopatología , Masculino , Polisomnografía , Postura , Apnea Central del Sueño/genéticaRESUMEN
Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
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Cromatina/metabolismo , Haploinsuficiencia/genética , Discapacidad Intelectual/genética , Transcripción Genética , Factor de Transcripción YY1/genética , Acetilación , Adolescente , Secuencia de Bases , Preescolar , Inmunoprecipitación de Cromatina , Estudios de Cohortes , Elementos de Facilitación Genéticos/genética , Femenino , Ontología de Genes , Haplotipos/genética , Hemicigoto , Histonas/metabolismo , Humanos , Linfocitos/metabolismo , Masculino , Metilación , Modelos Moleculares , Mutación Missense/genética , Unión Proteica/genética , Dominios Proteicos , Factor de Transcripción YY1/químicaRESUMEN
Next-generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type, and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype-phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Fenotipo , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Modelos Genéticos , Modelos Estadísticos , Reproducibilidad de los ResultadosRESUMEN
Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Portadoras/genética , Anomalías Craneofaciales/genética , Proteínas de Drosophila/genética , Discapacidad Intelectual/genética , Discapacidades para el Aprendizaje/genética , Mutación , Adolescente , Animales , Proteínas Portadoras/metabolismo , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico , Drosophila/genética , Drosophila/fisiología , Proteínas de Drosophila/metabolismo , Femenino , Habituación Psicofisiológica , Humanos , Discapacidad Intelectual/diagnóstico , Aprendizaje , Discapacidades para el Aprendizaje/diagnóstico , Masculino , Fenotipo , Síndrome , Adulto JovenRESUMEN
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.