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1.
Nat Commun ; 10(1): 4679, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616000

RESUMO

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

2.
J Med Genet ; 56(10): 654-661, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31040167

RESUMO

BACKGROUND: This study evaluates 6 years of prenatal rasopathy testing in the Netherlands, updates on previous data and gives recommendations for prenatal rasopathy testing. METHODS: 424 fetal samples, sent in for prenatal rasopathy testing in 2011-2016, were collected. Cohort 1 included 231 samples that were sequenced for 1-5 rasopathy genes. Cohort 2 included 193 samples that were analysed with a 14-gene next generation sequencing (NGS) panel. For all mutation-positive samples in both cohorts, the referring physician provided detailed ultrasound findings and postnatal follow-up. For 168 mutation-negative samples in cohort 2, solely clinical information on the requisition form was collected. RESULTS: In total, 40 (likely) pathogenic variants were detected (9.4%). All fetuses showed a variable degree of involvement of prenatal findings: increased nuchal translucency (NT)/cystic hygroma, distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies. An increased NT was the most common finding. Eight fetuses showed solely an increased NT/cystic hygroma, which were all larger than 5.5 mm. Ascites and renal anomalies appeared to be poor predictors of pathogenic outcome. CONCLUSION: Fetuses with a rasopathy show in general multiple ultrasound findings. The larger the NT and the longer it persists, the more likely it is to find a pathogenic variant. Rasopathy testing is recommended when the fetus shows an isolated increased NT ≥5.0 mm or when NT of ≥3.5 mm and at least one of the following ultrasound anomalies is present: distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies.

3.
Hum Genet ; 138(1): 61-72, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30535804

RESUMO

ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2.


Assuntos
Biomarcadores/análise , Predisposição Genética para Doença , Perda Auditiva/genética , Mutação , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Adulto Jovem
4.
Epilepsia ; 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30525188

RESUMO

OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.

5.
Cilia ; 7: 1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30479745

RESUMO

Background: Mainzer-Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions: By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer-Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.

6.
Eur J Hum Genet ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291343

RESUMO

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.

7.
Am J Hum Genet ; 103(1): 74-88, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29961571

RESUMO

In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs∗22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons.

8.
Hum Genet ; 2018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29754270

RESUMO

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

9.
Eur J Hum Genet ; 25(10): 1126-1133, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28905882

RESUMO

Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34 bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1Δ) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Δ promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2Δ)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia.


Assuntos
Atresia das Cóanas/genética , Surdez/congênito , Deleção de Genes , Cardiopatias Congênitas/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Atresia das Cóanas/diagnóstico , Surdez/diagnóstico , Surdez/genética , Facies , Feminino , Cardiopatias Congênitas/diagnóstico , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Regiões Promotoras Genéticas
10.
Genet Med ; 19(6): 667-675, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28574513

RESUMO

PURPOSE: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a first-tier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome- or genome-wide approach with a single test. METHODS: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting. RESULTS: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of ~2% (ranging from 0 to -5.8% per disorder). CONCLUSIONS: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.Genet Med advance online publication 27 October 2016.


Assuntos
Variações do Número de Cópias de DNA , Exoma , Doenças Genéticas Inatas/genética , Sequenciamento Completo do Genoma , Estudos de Coortes , Genoma Humano , Humanos , Padrões de Herança , Masculino , Polimorfismo de Nucleotídeo Único
11.
Eur J Hum Genet ; 25(7): 823-831, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28594414

RESUMO

RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , GTP Fosfo-Hidrolases/genética , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/genética , Proteínas de Membrana/genética , Síndrome de Noonan/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Fenótipo
12.
J Med Genet ; 54(9): 624-632, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28442542

RESUMO

BACKGROUND: Recent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP). METHODS: Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells. RESULTS: In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base. CONCLUSIONS: This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação de Sentido Incorreto , Retinite Pigmentosa/genética , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Adulto , Cerebelo/anormalidades , Anormalidades do Olho/genética , Feminino , Humanos , Doenças Renais Císticas/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Domínios Proteicos/genética , Retina/anormalidades
13.
Genet Med ; 19(9): 1055-1063, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28333917

RESUMO

PURPOSE: Implementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation. METHODS: We studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene-based testing) and WES simultaneously. RESULTS: Our unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted. CONCLUSION: Our data support such a use of WES in pediatric neurology for disorders of presumed genetic origin.Genet Med advance online publication 23 March 2017.


Assuntos
Testes Genéticos , Neurologia/métodos , Neurologia/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Pediatria/métodos , Pediatria/estatística & dados numéricos , Sequenciamento Completo do Exoma , Adolescente , Criança , Pré-Escolar , Análise Custo-Benefício , Feminino , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Humanos , Lactente , Masculino , Padrão de Cuidado/economia , Padrão de Cuidado/normas , Padrão de Cuidado/estatística & dados numéricos , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Exoma/estatística & dados numéricos
14.
Eur J Hum Genet ; 25(5): 591-599, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28224992

RESUMO

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.


Assuntos
Exoma , Oftalmopatias Hereditárias/genética , Padrões de Herança , Transtornos da Visão/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Oftalmopatias Hereditárias/patologia , Humanos , Países Baixos , Transtornos da Visão/patologia
15.
Hear Res ; 347: 56-62, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28089734

RESUMO

DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.


Assuntos
Códon sem Sentido , Mutação da Fase de Leitura , Perda Auditiva Neurossensorial/genética , Audição/genética , Proteínas dos Microfilamentos/genética , Limiar Auditivo , Análise Mutacional de DNA , Marcadores Genéticos , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/fisiopatologia , Perda Auditiva Neurossensorial/psicologia , Testes Auditivos , Hereditariedade , Humanos , Linhagem , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença
16.
Eur J Hum Genet ; 25(3): 308-314, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28000701

RESUMO

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.


Assuntos
Exoma , Testes Genéticos/estatística & dados numéricos , Perda Auditiva/genética , Análise de Sequência de DNA/estatística & dados numéricos , Conexinas/genética , Variações do Número de Cópias de DNA , Proteínas da Matriz Extracelular/genética , Proteínas Ligadas por GPI/genética , Testes Genéticos/normas , Perda Auditiva/diagnóstico , Perda Auditiva/epidemiologia , Humanos , Proteínas de Membrana/genética , Mutação , Cadeias Pesadas de Miosina/genética , Miosinas/genética , Países Baixos , Análise de Sequência de DNA/normas
17.
Genome Med ; 8(1): 131, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27964749

RESUMO

BACKGROUND: Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder. METHODS: Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies. RESULTS: In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 × 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. CONCLUSIONS: We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases.


Assuntos
Agenesia do Corpo Caloso/genética , Sequência de Bases , Transtornos Dismórficos Corporais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deleção de Sequência , Fatores de Transcrição/genética , Agenesia do Corpo Caloso/patologia , Transtornos Dismórficos Corporais/patologia , Criança , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Recém-Nascido , Masculino
19.
Am J Hum Genet ; 99(3): 711-719, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27545680

RESUMO

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.


Assuntos
Encéfalo/embriologia , Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Genes Essenciais/genética , Deficiência Intelectual/genética , Antígenos de Histocompatibilidade Menor/genética , Mutação/genética , Processamento de RNA/genética , Animais , Encéfalo/anormalidades , Encéfalo/patologia , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Feminino , Haploinsuficiência/genética , Cabeça/anormalidades , Heterozigoto , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Antígenos de Histocompatibilidade Menor/análise , Antígenos de Histocompatibilidade Menor/metabolismo , Linhagem , RNA Mensageiro/análise , Coluna Vertebral/anormalidades , Síndrome , Peixe-Zebra/anormalidades , Peixe-Zebra/embriologia , Peixe-Zebra/genética
20.
Nat Neurosci ; 19(9): 1194-6, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27479843

RESUMO

To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.


Assuntos
Deficiência Intelectual/genética , Mutação/genética , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Proteína 4 Homóloga a Disks-Large , Exoma/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Menor/genética , Fenótipo , Proteínas Quinases/genética , Proteína Fosfatase 2C/genética , Fatores de Transcrição SOXD/genética , Proteína Smad6/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Proteínas rac1 de Ligação ao GTP/genética
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