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1.
Clin Genet ; 105(3): 294-301, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38044714

RESUMEN

Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under-reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals.


Asunto(s)
Discapacidad Intelectual , Factores de Transcripción , Humanos , Encéfalo/metabolismo , Proteínas de Unión al Calcio/genética , Genotipo , Discapacidad Intelectual/genética , Fenotipo , Transactivadores/genética , Factores de Transcripción/genética
2.
Clin Genet ; 105(6): 655-660, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38384171

RESUMEN

Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome.


Asunto(s)
Deleción Cromosómica , Duplicación Cromosómica , Cromosomas Humanos Par 9 , Metilación de ADN , Cardiopatías Congénitas , N-Metiltransferasa de Histona-Lisina , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Metilación de ADN/genética , Cromosomas Humanos Par 9/genética , Masculino , Femenino , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Duplicación Cromosómica/genética , Niño , Preescolar , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Adolescente , Fenotipo
3.
Hum Reprod ; 39(1): 177-189, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37953503

RESUMEN

STUDY QUESTION: Is it possible to find the cause of primary ovarian insufficiency (POI) in more women by extensive screening? SUMMARY ANSWER: Adding next generation sequencing techniques including a POI-associated gene panel, extended whole exome sequencing data, as well as specific autoantibody assays to the recommended diagnostic investigations increased the determination of a potential etiological diagnosis of POI from 11% to 41%. WHAT IS KNOWN ALREADY: POI affects ∼1% of women. Clinical presentations and pathogenic mechanisms are heterogeneous and include genetic, autoimmune, and environmental factors, but the underlying etiology remains unknown in the majority of cases. STUDY DESIGN, SIZE, DURATION: Prospective cross-sectional study of 100 women with newly diagnosed POI of unknown cause consecutively referred to Haukeland University Hospital, Bergen, Norway, January 2019 to December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to standard recommended diagnostic investigations including screening for chromosomal anomalies and premutations in the fragile X mental retardation 1 gene (FMR1) we used whole exome sequencing, including targeted analysis of 103 ovarian-related genes, and assays of autoantibodies against steroid cell antigens. MAIN RESULTS AND THE ROLE OF CHANCE: We identified chromosomal aberrations in 8%, FMR1 premutations in 3%, genetic variants related to POI in 16%, and autoimmune POI in 3%. Furthermore in 11% we identified POI associated genetic Variants of unknown signifcance (VUS). A homozygous pathogenic variant in the ZSWIM7 gene (NM_001042697.2) was found in two women, corroborating this as a novel cause of monogenic POI. No associations between phenotypes and genotypes were found. LIMITATIONS, REASONS FOR CAUTION: Use of candidate genetic and autoimmune markers limit the possibility to discover new markers. To further investigate the genetic variants, family studies would have been useful. We found a relatively high proportion of genetic variants in women from Africa and lack of genetic diversity in the genomic databases can impact diagnostic accuracy. WIDER IMPLICATIONS OF THE FINDINGS: Since no specific clinical or biochemical markers predicted the underlying cause of POI discussion of which tests should be part of diagnostic screening in clinical practice remains open. New technology has altered the availability and effectiveness of genetic testing, and cost-effectiveness analyses are required to aid sustainable diagnostics. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants and fellowships from Stiftelsen Kristian Gerhard Jebsen, the Novonordisk Foundation, the Norwegian Research Council, University of Bergen, and the Regional Health Authorities of Western Norway. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT04082169.


Asunto(s)
Insuficiencia Ovárica Primaria , Humanos , Femenino , Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/genética , Mutación , Estudios Transversales , Autoanticuerpos , Estudios Prospectivos , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética
4.
Clin Genet ; 103(6): 717-719, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36648078

RESUMEN

Trichorhinophalangeal syndromes (TRPSs) are rare hereditary syndromes with autosomal dominant inheritance. Patients exhibit abnormalities including bulbous pear-shaped nose, broad columella, and long and flat philtrum, fine, sparse, brittle, slow-growing scalp hair, skeletal abnormalities, and short stature. Three families; age at subependymoma surgery, pathogenic TRPS1(NM_014112.5) variant, and subependymoma number are described.


Asunto(s)
Glioma Subependimario , Síndrome de Langer-Giedion , Humanos , Síndrome , Síndrome de Langer-Giedion/patología , Nariz , Dedos/patología , Proteínas Represoras
5.
J Med Genet ; 59(2): 155-164, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-33443097

RESUMEN

BACKGROUND: Loss-of-function mutations in CDKN1C cause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene's PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on a boy with a remarkable mixture of both syndromes, with developmental delay and microcephaly as additional features. METHODS: Whole-exome DNA sequencing and ultra-deep RNA sequencing of leucocyte-derived and fibroblast-derived mRNA were performed in the family. RESULTS: We found a maternally inherited variant in the IMAGe hotspot region: NM_000076.2(CDKN1C) c.822_826delinsGAGCTG. The asymptomatic mother had inherited this variant from her mosaic father with mild BWS features. This delins caused tissue-specific frameshifting resulting in at least three novel mRNA transcripts in the boy. First, a splice product causing CDKN1C truncation was the likely cause of BWS. Second, an alternative splice product in fibroblasts encoded IMAGe-associated amino acid substitutions. Third, we speculate that developmental delay is caused by a change in the alternative CDKN1C-201 (ENST00000380725.1) transcript, encoding a novel isoform we call D (UniProtKB: A6NK88). Isoform D is distinguished from isoforms A and B by alternative splicing within exon 1 that changes the reading frame of the last coding exon. Remarkably, this delins changed the reading frame back to the isoform A/B type, resulting in a hybrid D-A/B isoform. CONCLUSION: Three different cell-type-dependent RNA products can explain the co-occurrence of both BWS and IMAGe features in the boy. Possibly, brain expression of hybrid isoform D-A/B is the cause of developmental delay and microcephaly, a phenotypic feature not previously reported in CDKN1C patients.


Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Discapacidades del Desarrollo/genética , Mutación , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Humanos , Recién Nacido , Masculino , Microcefalia/genética , Isoformas de Proteínas/genética , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Eliminación de Secuencia , Síndrome , Secuenciación Completa del Genoma
6.
Clin Genet ; 102(3): 182-190, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35662002

RESUMEN

While inherited hemizygous variants in PHF6 cause X-linked recessive Borjeson-Forssman-Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies. We observed skewed X-inactivation in blood and streaky skin pigmentation compatible with functional mosaicism. Variants occurred de novo in 10 individuals, of whom one was only mildly affected and transmitted it to her more severely affected daughter. The mutational spectrum comprises a two-exon deletion, five truncating, one splice-site and three missense variants, the latter all located in the PHD2 domain and predicted to severely destabilize the domain structure. This observation supports the hypothesis of more severe variants in females contributing to gender-specific phenotypes in addition to or in combination with effects of X-inactivation and functional mosaicism. Therefore, our findings further delineate the clinical and mutational spectrum of female BFLS and provide further insights into possible genotype-phenotype correlations between females and males.


Asunto(s)
Hipogonadismo , Discapacidad Intelectual , Discapacidad Intelectual Ligada al Cromosoma X , Anomalías Musculoesqueléticas , Proteínas Represoras , Epilepsia , Cara/anomalías , Femenino , Dedos/anomalías , Trastornos del Crecimiento , Humanos , Hipogonadismo/genética , Discapacidad Intelectual/complicaciones , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Anomalías Musculoesqueléticas/complicaciones , Obesidad , Proteínas Represoras/genética
7.
Am J Med Genet A ; 188(4): 1065-1074, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34921505

RESUMEN

Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low-risk variants. Four Zn-finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn-finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2-related phenotypic variability. The most prevalent phenotypic feature is post-axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.


Asunto(s)
Holoprosencefalia , Hipopituitarismo , Holoprosencefalia/genética , Humanos , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Mutación , Proteínas Nucleares/genética , Fenotipo , Zinc , Proteína Gli2 con Dedos de Zinc/genética
8.
Hum Mutat ; 42(6): 745-761, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33942428

RESUMEN

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical, and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction, and immuno-hematological problems are emerging phenotypes in KARS1-related disorder. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients.


Asunto(s)
Anomalías Múltiples/genética , Lisina-ARNt Ligasa/genética , Anomalías Múltiples/metabolismo , Anomalías Múltiples/patología , Adolescente , Alelos , Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/patología , Niño , Preescolar , Estudios de Cohortes , Citosol/metabolismo , Progresión de la Enfermedad , Femenino , Homocigoto , Humanos , Lactante , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Microcefalia/complicaciones , Microcefalia/genética , Microcefalia/patología , Mitocondrias/genética , Mitocondrias/metabolismo , Organismos Modificados Genéticamente , Linaje , Fenotipo , Saccharomyces cerevisiae
9.
Am J Hum Genet ; 103(5): 752-768, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388402

RESUMEN

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.


Asunto(s)
Haploinsuficiencia/genética , Discapacidad Intelectual/genética , Megalencefalia/genética , Factores de Transcripción NFI/genética , Adolescente , Adulto , Animales , Corteza Cerebral/patología , Niño , Preescolar , Codón sin Sentido/genética , Estudios de Cohortes , Cuerpo Calloso/patología , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple/genética , Adulto Joven
10.
Genet Med ; 23(7): 1315-1324, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33864021

RESUMEN

PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype-genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.


Asunto(s)
Hidropesía Fetal , Receptor EphB4 , Estudios de Asociación Genética , Humanos , Fenotipo , Fosforilación , Receptor EphB4/genética
11.
Int J Mol Sci ; 22(11)2021 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-34070858

RESUMEN

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.


Asunto(s)
Demencia Frontotemporal/genética , Genes Dominantes , Genes Recesivos , Ataxias Espinocerebelosas/genética , Ubiquitina-Proteína Ligasas , Adulto , Edad de Inicio , Anciano , Familia , Femenino , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Expresión Génica , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Pliegue de Proteína , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patología
12.
Genet Med ; 22(1): 124-131, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31316167

RESUMEN

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.


Asunto(s)
Aracnodactilia/diagnóstico , Contractura/diagnóstico , Fibrilina-2/genética , Análisis de Secuencia de ADN/métodos , Aracnodactilia/genética , Niño , Contractura/genética , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Pruebas Genéticas , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Fenotipo , Estudios Retrospectivos , Sensibilidad y Especificidad
13.
Tidsskr Nor Laegeforen ; 140(6)2020 04 21.
Artículo en Noruego | MEDLINE | ID: mdl-32321218

RESUMEN

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant genetic disorder characterised by pulmonary cysts, fibrofolliculomas and renal tumours. The pulmonary cysts may lead to pneumothorax, and in cases of primary, spontaneous pneumothorax the syndrome should be excluded. The renal tumours are frequently malignant, but slow-growing. Screening and family assessment enable discovery of renal cancer at an early stage. The syndrome is underdiagnosed and little known.


Asunto(s)
Síndrome de Birt-Hogg-Dubé , Neoplasias Renales , Enfermedades Pulmonares , Neumotórax , Neoplasias Cutáneas , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neumotórax/etiología , Neumotórax/genética
14.
Genet Med ; 21(12): 2723-2733, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31239556

RESUMEN

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.


Asunto(s)
Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Trastornos del Neurodesarrollo/genética , Animales , Niño , Cromatina/genética , Cromatina/metabolismo , Discapacidades del Desarrollo/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación/genética , Mutación Missense/genética , Trastornos del Neurodesarrollo/metabolismo , Factores de Transcripción/genética , Secuenciación del Exoma/métodos , Adulto Joven
16.
Am J Hum Genet ; 91(2): 252-64, 2012 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-22840365

RESUMEN

We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.


Asunto(s)
Cromosomas Humanos X/genética , Variaciones en el Número de Copia de ADN/genética , Reordenamiento Génico/genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Mapeo Cromosómico , Cromosomas Artificiales Bacterianos/genética , Hibridación Genómica Comparativa , Biología Computacional , Replicación del ADN/genética , Duplicación de Gen/genética , Humanos , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple/genética , Recombinación Genética/genética , Proteínas Supresoras de Tumor
17.
Am J Med Genet C Semin Med Genet ; 166C(3): 290-301, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25099957

RESUMEN

Recently, de novo aberrations in PHF6 were identified in females with intellectual disability and with a distinct phenotype including a characteristic facial gestalt with bitemporal narrowing, prominent supraorbital ridges, synophrys, a short nose and dental anomalies, tapering fingers with brachytelephalangy, clinodactyly and hypoplastic nails, short toes with hypoplastic nails, and linear skin hyperpigmentation. In adolescent or older patients, this phenotype overlaps but is not identical with Borjeson-Forssman-Lehmann syndrome in males, caused by X-linked recessive mutations in PHF6. In younger girls there seems to be a striking phenotypic overlap with Coffin-Siris syndrome, which is characterized by intellectual disability, sparse hair and hypoplastic nails. This review will summarize and characterize the female phenotype caused by de novo aberrations in PHF6 and will discuss the overlapping and distinguishing features with Coffin-Siris syndrome.


Asunto(s)
Anomalías Múltiples/etiología , Proteínas Portadoras/genética , Epilepsia/etiología , Cara/anomalías , Dedos/anomalías , Trastornos del Crecimiento/etiología , Deformidades Congénitas de la Mano/etiología , Hipogonadismo/etiología , Discapacidad Intelectual/etiología , Discapacidad Intelectual Ligada al Cromosoma X/etiología , Micrognatismo/etiología , Cuello/anomalías , Obesidad/etiología , Anomalías Múltiples/genética , Niño , Epilepsia/genética , Femenino , Estudios de Asociación Genética , Trastornos del Crecimiento/genética , Deformidades Congénitas de la Mano/genética , Humanos , Hipogonadismo/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Micrognatismo/genética , Uñas Malformadas/genética , Obesidad/genética , Linaje , Proteínas Represoras , Adulto Joven
18.
Am J Med Genet A ; 164A(7): 1622-6, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24678003

RESUMEN

MEIS2 is a homeodomain-containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause cleft palate [Crowley et al. (2010); Am J Med Genet 152A:1326-1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions.


Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Estudios de Asociación Genética , Haploinsuficiencia , Proteínas de Homeodominio/genética , Discapacidades para el Aprendizaje/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Aberraciones Cromosómicas , Labio Leporino/diagnóstico , Fisura del Paladar/diagnóstico , Hibridación Genómica Comparativa , Facies , Femenino , Humanos , Discapacidades para el Aprendizaje/diagnóstico , Masculino , Fenotipo , Análisis de Secuencia de ADN , Adulto Joven
19.
Artículo en Inglés | MEDLINE | ID: mdl-38963811

RESUMEN

PURPOSE: Congenital hyperinsulinism (CHI) is a rare, monogenic disease characterized by excessive insulin secretion. We aimed to evaluate all probands with suspected CHI in Norway registered over the past two decades. METHODS: The study included 98 probands. Clinical data were cumulated from medical records. All probands were screened for variants in the genes ABCC8 and KCNJ11. Other CHI-related genes were Sanger-sequenced as indicated by the patients' phenotype (N=75) or analyzed by next-generation sequencing employing a panel of 30 CHI-related genes (N=23). RESULTS: Twenty-one probands (21%) received a diagnosis other than CHI, the most common being idiopathic ketotic hypoglycemia (9%) or syndromic hyperinsulinism (4%). In the final cohort of 77 CHI probands, genetic findings were revealed in 46 (60%). ABCC8 variants were most common (N=40) and five novel variants were identified. One proband harbored both the pathogenic GCK variant p.(Ala456Val) and the ABCC8 variant p.(Gly505Cys). Although most ABCC8 variants caused immediate disease onset with severe hypoglycemia and were diazoxide-unresponsive, eight probands had a heterozygous, apparently dominant variant with milder phenotype. Two probands had pathogenic variants in GLUD1, whereas variants in HADH, HNF4A, KCNJ11, and HK1 were identified in one proband each, the latter being non-coding. Neurologic sequelae were reported in 53% of the CHI probands. Of non-surgically treated probands, 43% had spontaneous resolution. The minimum birth prevalence of CHI in Norway is 1:19,400 live births. MAIN CONCLUSIONS: Individuals with disease-causing ABCC8 variants dominated our cohort. Patients with known genetic etiology had earlier and more severe disease-onset than genetically unsolved patients.

20.
Pediatrics ; 153(6)2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38808412

RESUMEN

Molybdenum cofactor deficiency classically presents in neonates with intractable seizures; however, milder cases generally present before age 2 years with developmental delays and may go undiagnosed. Early diagnosis, and safe, US Food and Drug Administration-approved substrate replacement are critical to preserve neurologic function. This article discusses 2 children who presented with late-onset molybdenum cofactor deficiency type A.


Asunto(s)
Discapacidades del Desarrollo , Errores Innatos del Metabolismo de los Metales , Humanos , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/diagnóstico , Errores Innatos del Metabolismo de los Metales/complicaciones , Errores Innatos del Metabolismo de los Metales/diagnóstico , Molibdoferredoxina
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