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PURPOSE: Structural variants (SVs) play an important role in inherited retinal diseases (IRD). Although the identification of SVs significantly improved upon the availability of genome sequencing, it is expected that involvement of SVs in IRDs is higher than anticipated. We revisited short-read genome sequencing data to enhance the identification of gene-disruptive SVs. METHODS: Optical genome mapping was performed to improve SV detection in short-read genome sequencing-negative cases. In addition, reanalysis of short-read genome sequencing data was performed to improve the interpretation of SVs and to re-establish SV prioritization criteria. RESULTS: In a monoallelic USH2A case, optical genome mapping identified a pericentric inversion (173 megabase), with 1 breakpoint disrupting USH2A. Retrospectively, the variant could be observed in genome sequencing data but was previously deemed false positive. Reanalysis of short-read genome sequencing data (427 IRD cases) was performed which yielded 30 pathogenic SVs affecting, among other genes, USH2A (n = 15), PRPF31 (n = 3), and EYS (n = 2). Eight of these (>25%) were overlooked during previous analyses. CONCLUSION: Critical evaluation of our findings allowed us to re-establish and improve our SV prioritization and interpretation guidelines, which will prevent missing pathogenic events in future analyses. Our data suggest that more attention should be paid to SV interpretation and the current contribution of SVs in IRDs is still underestimated.
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Genoma Humano , Enfermedades de la Retina , Humanos , Estudios Retrospectivos , Genoma Humano/genética , Mapeo Cromosómico , Análisis de Secuencia , Enfermedades de la Retina/genética , Variación Estructural del Genoma , Proteínas del Ojo/genéticaRESUMEN
Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, followed by the degeneration of cone photoreceptors. As a result of photoreceptor degeneration, affected individuals experience gradual loss of visual function, with primary symptoms of progressive nyctalopia, constricted visual fields and, ultimately, central vision loss. The onset, severity and clinical course of RP shows great variability and unpredictability, with most patients already experiencing some degree of visual disability in childhood. While RP is currently untreatable for the majority of patients, significant efforts have been made in the development of genetic therapies, which offer new hope for treatment for patients affected by inherited retinal dystrophies. In this exciting era of emerging gene therapies, it remains imperative to continue supporting patients with RP using all available options to manage their condition. Patients with RP experience a wide variety of physical, mental and social-emotional difficulties during their lifetime, of which some require timely intervention. This review aims to familiarize readers with clinical management options that are currently available for patients with RP.
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Ceguera Nocturna , Distrofias Retinianas , Retinitis Pigmentosa , Humanos , Retinitis Pigmentosa/genética , Células Fotorreceptoras Retinianas Conos , Células Fotorreceptoras Retinianas BastonesRESUMEN
An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.
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Metilación de ADN , Trastornos del Neurodesarrollo , Islas de CpG/genética , Metilación de ADN/genética , ADN Intergénico , Epigénesis Genética , Humanos , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , SíndromeRESUMEN
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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Defectos de la Visión Cromática , Canales Catiónicos Regulados por Nucleótidos Cíclicos , Defectos de la Visión Cromática/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Humanos , Mutación , Células Fotorreceptoras Retinianas ConosRESUMEN
Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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ADN Helicasas/genética , Discapacidad Intelectual/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Dominio Catalítico , Niño , Preescolar , Estudios de Cohortes , Epilepsia/genética , Femenino , Genes Dominantes , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Trastornos del Neurodesarrollo/fisiopatología , Linaje , Adulto JovenRESUMEN
KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.
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Trastornos del Movimiento/genética , Trastornos del Neurodesarrollo/genética , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Adolescente , Adulto , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/psicología , Niño , Preescolar , Fenómenos Electrofisiológicos , Exoma , Mutación del Sistema de Lectura , Variación Genética , Haploinsuficiencia , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/psicología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/psicología , Mutación Missense/genética , Trastornos del Neurodesarrollo/psicología , Técnicas de Placa-Clamp , Sustancia Blanca/anomalías , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.
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Análisis Costo-Beneficio , Exones/genética , Proteínas de la Matriz Extracelular/genética , Sondas Moleculares/metabolismo , Sitios de Empalme de ARN/genética , Retinitis Pigmentosa/genética , Análisis de Secuencia de ADN , Síndromes de Usher/genética , Secuencia de Bases , Variaciones en el Número de Copia de ADN/genética , Eliminación de Gen , Humanos , Polimorfismo de Nucleótido Simple/genética , Retinitis Pigmentosa/economía , Síndromes de Usher/economíaRESUMEN
Perrault syndrome (PS) is a rare recessive disorder characterized by ovarian dysgenesis and sensorineural deafness. It is clinically and genetically heterogeneous, and previously mutations have been described in different genes, mostly related to mitochondrial proteostasis. We diagnosed three unrelated females with PS and set out to identify the underlying genetic cause using exome sequencing. We excluded mutations in the known PS genes, but identified a single homozygous mutation in the ERAL1 gene (c.707A > T; p.Asn236Ile). Since ERAL1 protein binds to the mitochondrial 12S rRNA and is involved in the assembly of the small mitochondrial ribosomal subunit, the identified variant represented a likely candidate. In silico analysis of a 3D model for ERAL1 suggested that the mutated residue hinders protein-substrate interactions, potentially affecting its function. On a molecular basis, PS skin fibroblasts had reduced ERAL1 protein levels. Complexome profiling of the cells showed an overall decrease in the levels of assembled small ribosomal subunit, indicating that the ERAL1 variant affects mitochondrial ribosome assembly. Moreover, levels of the 12S rRNA were reduced in the patients, and were rescued by lentiviral expression of wild type ERAL1. At the physiological level, mitochondrial respiration was markedly decreased in PS fibroblasts, confirming disturbed mitochondrial function. Finally, knockdown of the C. elegans ERAL1 homologue E02H1.2 almost completely blocked egg production in worms, mimicking the compromised fertility in PS-affected women. Our cross-species data in patient cells and worms support the hypothesis that mutations in ERAL1 can cause PS and are associated with changes in mitochondrial metabolism.
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Proteínas de Unión al GTP/genética , Disgenesia Gonadal 46 XX/genética , Pérdida Auditiva Sensorineural/genética , Proteínas de Unión al ARN/genética , Secuencia de Aminoácidos/genética , Animales , Caenorhabditis elegans/genética , Exoma , Femenino , Proteínas de Unión al GTP/metabolismo , Disgenesia Gonadal 46 XX/metabolismo , Pérdida Auditiva Sensorineural/metabolismo , Homocigoto , Humanos , Mitocondrias/genética , Proteínas Mitocondriales/metabolismo , Chaperonas Moleculares/metabolismo , Mutación , Mutación Missense/genética , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Proteínas de Unión al ARN/metabolismo , Secuenciación del ExomaRESUMEN
PURPOSE: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive. METHODS: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot. RESULTS: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function. CONCLUSIONS: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.
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Prolil Hidroxilasas/genética , Transcetolasa/genética , Proteasas Ubiquitina-Específicas/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Epilepsia/genética , Exoma , Anomalías del Ojo/genética , Femenino , Humanos , Hipoventilación/genética , Discapacidad Intelectual/genética , Mutación con Pérdida de Función/genética , Masculino , Hipotonía Muscular/genética , Linaje , Fenotipo , Disautonomías Primarias/genética , Prolil Hidroxilasas/metabolismo , Síndrome , Transcetolasa/metabolismo , Secuenciación del Exoma , Adulto JovenRESUMEN
Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
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Anomalías Múltiples/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Factores de Transcripción NFI/genética , Síndrome de Sotos/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/fisiopatología , Niño , Preescolar , Deleción Cromosómica , Hipotiroidismo Congénito/fisiopatología , Anomalías Craneofaciales/fisiopatología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Exones/genética , Femenino , Deformidades Congénitas de la Mano/fisiopatología , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatología , Mutación Missense/genética , Fenotipo , Displasia Septo-Óptica/genética , Displasia Septo-Óptica/fisiopatología , Síndrome de Sotos/fisiopatología , Adulto JovenRESUMEN
Ocular albinism type 1 (OA1) is caused by mutations in the GPR143 gene located at Xp22.2. The manifestations, which are due to hypopigmentation, are confined to the eyes and optic pathway. OA1 associated with late-onset sensorineural hearing loss was previously reported in a single family and hypothesized to be caused by a contiguous gene deletion syndrome involving GPR143 and the adjacent gene, TBL1X. Here, we report on a family with OA1, infertility, late-onset sensorineural hearing loss, and a small interstitial Xp microdeletion including the GPR143, TBL1X, and SHROOM2 genes. In addition, we re-examined a patient previously described with OA1, infertility and a similar Xp deletion with audiologic follow-up showing a late-onset sensorineural hearing loss. Our results raise an intriguing question about the possibility for TBL1X (absence) involvement in this type of hearing loss. However, our study cannot claim a causative relationship and more convincing evidence is needed before the hypothesis can be accepted that TBL1X could be involved in late-onset sensorineural hearing loss and that ocular albinism with late-onset sensorineural hearing loss can present itself as a contiguous gene deletion/microdeletion syndrome. The finding of infertility in all affected male patients demonstrates that this deletion, including the SHROOM2 gene, may be a potentially causative X-linked genetic factor of male infertility.
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Albinismo Ocular/patología , Proteínas del Ojo/genética , Pérdida Auditiva Sensorineural/patología , Infertilidad/patología , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Mutación , Transducina/genética , Adulto , Anciano , Albinismo Ocular/complicaciones , Albinismo Ocular/genética , Femenino , Eliminación de Gen , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/genética , Humanos , Infertilidad/complicaciones , Infertilidad/genética , Masculino , Persona de Mediana Edad , LinajeRESUMEN
The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability, and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients. The variant, p.R514H, is located in the forkhead-box DNA-binding domain and is equivalent to the well-studied p.R553H FOXP2 variant that cosegregates with CAS in a large UK family. We present here for the first time a direct comparison of the molecular and clinical consequences of the same mutation affecting the equivalent residue in FOXP1 and FOXP2. Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity, and deleterious effects on protein interactions. Nonetheless, clinical manifestations were broader and more severe in the three cases carrying the p.R514H FOXP1 variant than in individuals with the p.R553H variant related to CAS, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.
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Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Factores de Transcripción Forkhead/genética , Mutación Missense , Fenotipo , Proteínas Represoras/genética , Sustitución de Aminoácidos , Línea Celular , Niño , Preescolar , Femenino , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Genes Reporteros , Estudios de Asociación Genética , Genotipo , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Mutación con Pérdida de Función , Imagen por Resonancia Magnética , Masculino , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Secuenciación del ExomaRESUMEN
PURPOSE: To examine the long-term clinical course and variability in a large pedigree segregating CRB1 type autosomal recessive retinitis pigmentosa. METHODS: An observational case study of 30 patients with CRB1 type autosomal recessive retinitis pigmentosa, homozygous for the CRB1 c.3122T > C; p.(Met1041Thr) mutation from a Dutch genetically isolated population in which the CRB1 gene was originally identified. The authors evaluated medical records, analyzed a questionnaire, and performed a comprehensive ophthalmic examination, including optical coherence tomography. RESULTS: Mean follow-up was 19 years (range 0-45 years, SD 15 years). With aging, patients showed progressive visual decline, deterioration of visual fields, increasing narrowing of the anterior chamber, increased prevalence of cataract, and an increase in the amount of intraretinal pigmentations. Fifty percent of patients had a visual acuity of ≤0.3 at Age 18 and of ≤0.1 at Age 35. Electroretinogram responses were severely reduced or absent already at a young age and optical coherence tomography showed increased retinal thickness with often cystoid maculopathy at young age, and thinning of the retina and disorientation of the photoreceptor layer in the late stages. The clinical course showed considerable interindividual variability, but intraindividual similarity between both eyes was the rule. CONCLUSION: The wide and variable clinical spectrum in patients with the same CRB1 mutation supports the hypothesis that the CRB1 type autosomal recessive retinitis pigmentosa-phenotype is modulated by other factors. The clinical variability will make it harder to evaluate the effect of (upcoming) therapies for retinitis pigmentosa, although because of the intraindividual similarity between both eyes, the contralateral eye can be used as an excellent internal control.
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Proteínas del Ojo/genética , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Anciano , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Retinitis Pigmentosa/fisiopatología , Tomografía de Coherencia Óptica , Trastornos de la Visión/etiología , Trastornos de la Visión/fisiopatología , Agudeza Visual/fisiología , Campos Visuales/fisiología , Adulto JovenRESUMEN
Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A. Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy. Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
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INPP5E encodes inositol polyphosphate-5-phosphatase E, an enzyme involved in regulating the phosphatidylinositol (PIP) makeup of the primary cilium membrane. Pathogenic variants in INPP5E hence cause a variety of ciliopathies: genetic disorders caused by dysfunctional cilia. While the majority of these disorders are syndromic, such as the neuronal ciliopathy Joubert syndrome, in some cases patients will present with an isolated phenotype-most commonly non-syndromic retinitis pigmentosa (RP). Here, we report two novel variants in INPP5E identified in two patients with non-syndromic RP: patient 1 with compound heterozygous variants (c.1516C > T, p.(Q506*), and c.847G > A, p.(A283T)) and patient 2 with a homozygous variant (c.1073C > T, p.(P358L)). To determine whether these variants were causative for the phenotype in the patients, automated ciliary phenotyping of patient-derived dermal fibroblasts was performed for percent ciliation, cilium length, retrograde IFT trafficking, and INPP5E localization. In both patients, a decrease in ciliary length and loss of INPP5E localization in the primary cilia were seen. With these molecular findings, we can confirm functionally that the novel variants in INPP5E are causative for the RP phenotypes seen in both patients. Additionally, this study demonstrates the usefulness of utilizing ciliary phenotyping as an assistant in ciliopathy diagnosis and phenotyping.
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Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy. Methods: Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases. Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%. Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.
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Secuenciación del Exoma , Fenotipo , Distrofias Retinianas , Humanos , Masculino , Distrofias Retinianas/genética , Distrofias Retinianas/epidemiología , Distrofias Retinianas/diagnóstico , Países Bajos/epidemiología , Femenino , Niño , Adolescente , Preescolar , Adulto Joven , Proteínas del Ojo/genética , Mutación , Proteínas del Citoesqueleto/genética , Lactante , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied. The DNAm episignature was developed with an Infinium Methylation EPIC BeadChip array analysis using peripheral blood cells. Support vector machine (SVM) modeling and clustering methods were employed to generate a DNAm classifier for PTHS. Validation was extended to an additional cohort of 11 individuals with PTHS. The episignature was assessed in relation to other neurodevelopmental disorders and its specificity was examined. A specific DNAm episignature for PTHS was established. The classifier exhibited high sensitivity for TCF4 haploinsufficiency and missense variants in the basic-helix-loop-helix domain. Notably, seven individuals with TCF4 variants exhibited negative episignatures, suggesting complexities related to mosaicism, genetic factors, and environmental influences. The episignature displayed degrees of overlap with other related disorders and biological pathways. This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negatively underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.
Asunto(s)
Metilación de ADN , Hiperventilación , Discapacidad Intelectual , Factor de Transcripción 4 , Humanos , Factor de Transcripción 4/genética , Hiperventilación/genética , Hiperventilación/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Femenino , Masculino , Niño , Facies , Adolescente , Epigenómica/métodos , Epigénesis Genética , Hipercinesia/genética , Preescolar , Adulto , Adulto JovenRESUMEN
Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.
Asunto(s)
Catarata/genética , Genotipo , Hipogonadismo/genética , Discapacidad Intelectual/genética , Mutación Missense , Fenotipo , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab3/genética , Secuencia de Aminoácidos , Animales , Catarata/patología , Niño , Preescolar , Humanos , Hipogonadismo/patología , Lactante , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Proteínas de Unión al GTP rab/química , Proteínas de Unión al GTP rab3/químicaRESUMEN
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.
Asunto(s)
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
Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.