RESUMEN
Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.
Asunto(s)
Cinesinas , Neuronas , Humanos , Animales , Ratones , Cinesinas/genética , Neuronas/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Apoptosis , Encéfalo/metabolismoRESUMEN
Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.
Asunto(s)
Genómica/métodos , Mutación , Trastornos del Neurodesarrollo/epidemiología , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Linaje , Prevalencia , Turquía/epidemiología , Secuenciación del Exoma , Adulto JovenRESUMEN
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
Asunto(s)
Eccema/diagnóstico , Eccema/genética , Predisposición Genética a la Enfermedad , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Histona Desacetilasas/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas Represoras/genética , Adolescente , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Eccema/patología , Exoma/genética , Facies , Femenino , Genoma Humano/genética , Genómica/métodos , Trastornos del Crecimiento/patología , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Microcefalia/patología , Fenotipo , Secuenciación del ExomaRESUMEN
The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.
Asunto(s)
División Celular Asimétrica/fisiología , Polaridad Celular/fisiología , Proteínas de la Membrana/genética , Microcefalia/virología , Neuronas/metabolismo , Proteínas Nucleares/genética , Animales , División Celular , Drosophila melanogaster/metabolismo , Humanos , Mutación , Células-Madre Neurales/metabolismo , Células-Madre Neurales/virología , Neuronas/citología , Virus ZikaRESUMEN
Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación Missense , Proteínas de Neoplasias/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , ARN Helicasas/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Secuenciación del ExomaRESUMEN
Al-Awadi-Raas-Rothschild syndrome (AARRS) is a rare autosomal recessive disorder which consists of severe malformations of the upper and lower limbs, abnormal genitalia and underdeveloped pelvis. Here, we present a fetus with severe limbs defects, including bilateral humeroradial synostosis, bilateral oligodactyly in hands, underdeveloped pelvis, short femora and tibiae, absence of fibulae, severely small feet, and absence of uterus. An autosomal recessively inherited novel mutation in WNT7A found in the fetus, c.304C > T, affects an evolutionarily well-conserved amino acid, causing the p.(R102W) missense change at protein level. The findings presented in this fetus are compatible with diagnosis of AARRS, expanding the mutational spectrum of limb malformations arising from defects in WNT7A.
Asunto(s)
Amenorrea/genética , Ectromelia/genética , Extremidades/fisiopatología , Huesos Pélvicos/anomalías , Útero/anomalías , Proteínas Wnt/genética , Amenorrea/fisiopatología , Ectromelia/fisiopatología , Femenino , Feto/fisiopatología , Humanos , Mutación Missense , Huesos Pélvicos/fisiopatología , Polidactilia/genética , Polidactilia/fisiopatología , Embarazo , Sinostosis/genética , Sinostosis/fisiopatología , Útero/fisiopatologíaRESUMEN
BACKGROUND/AIM: Neural tube defects (NTDs) are common congenital malformations that develop as a result of interactions between several genes and environmental factors. Many factors have been investigated in order to understand the etiology of NTDs, and many studies have identified folate intake as a common contributing factor. The exact etiology of the disease is still unknown. MATERIALS AND METHODS: In this study, we compared serum folate, vitamin B12, and homocysteine levels, along with common thrombophilia-related genetic variations, including factor V Leiden, factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C, in 35 pregnant women with fetal NTDs and 38 pregnant women with healthy fetuses. RESULTS: A significant difference in serum vitamin B12 level and factor V Leiden frequency was detected between the two groups. On the other hand, serum folate, homocysteine levels, and factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C were not significantly different in the NTD group compared to the controls. CONCLUSION: These results indicate that vitamin B12 supplementation along with folate may help in lowering NTD frequency. In addition, this is the first study that provides evidence for a possible relationship between increased NTD risk and factor V Leiden.
Asunto(s)
Defectos del Tubo Neural , Femenino , Ácido Fólico , Genotipo , Homocisteína , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2) , Mutación , Embarazo , Protrombina , Vitamina B 12RESUMEN
PURPOSE: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited. METHODS: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed. RESULTS: Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent. CONCLUSION: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Cardiopatías Congénitas/genética , Síndrome de Noonan/genética , Proteínas ras/genética , Cardiomiopatía Hipertrófica/patología , Femenino , Estudios de Asociación Genética , Genotipo , Mutación de Línea Germinal , Cardiopatías Congénitas/patología , Humanos , Masculino , Síndrome de Noonan/patología , Linaje , FenotipoRESUMEN
BACKGROUND: To assess Factor V Leiden (FVL) (rs6025), Prothrombin G20210A (rs1799963), MTHFR C677T (rs1801133), and MTHFR A1298C (rs1801131) gene mutations as risk factors in the development of retinopathy of prematurity (ROP). MATERIALS AND METHODS: A total of 105 children were included in this cross-sectional study. Patients were divided into two groups. The study group consisted of 55 infants with a history of ROP and the control group comprised 50 healthy infants with term birth. All subjects were screened for the presence of certain mutations (FVL, Prothrombin G20210A, MTHFR C677T and MTHFR A1298C) by Real-Time PCR at 1 year of age. RESULTS: The mean gestational age (GA) and birth weight (BW) of the study group were, 28.65 ± 2.85 weeks and 1171 ± 385.74 g, respectively. There were no significant differences of genotype and allele frequency of Prothrombin G20210A, MTHFR A1298C and MTHFR C677T between the study and control groups (p > 0.05). Eight children (14.5 %) had heterozygous and one child (1.8%) had homozygous FVL mutation in the study group. One child (2%) in the control group had heterozygous FVL mutation. There was statistically significant differences of FVL allele and genotype frequencies between the groups (p < 0.05). CONCLUSIONS: The prevalence of FVL polymorphism (16.3 %) was higher in ROP patients than control subjects in this Turkish cohort. We suggest a possible association of FVL mutation with ROP at the end of the study.
Asunto(s)
Factor V/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Protrombina/genética , Retinopatía de la Prematuridad/genética , Peso al Nacer , Estudios Transversales , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Edad Gestacional , Voluntarios Sanos , Humanos , Lactante , Masculino , Prevalencia , Reacción en Cadena en Tiempo Real de la Polimerasa , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/epidemiología , Factores de Riesgo , Turquía/epidemiologíaAsunto(s)
Cerebelo/anomalías , Hidrocefalia/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Ultrasonografía Prenatal , Aborto Inducido , Adulto , Vermis Cerebeloso/anomalías , Vermis Cerebeloso/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Cisterna Magna/anomalías , Cisterna Magna/diagnóstico por imagen , Femenino , Humanos , Embarazo , Segundo Trimestre del Embarazo , Rombencéfalo/anomalías , Rombencéfalo/diagnóstico por imagenRESUMEN
BACKGROUND: Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS: We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS: Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION: In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING: This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.
Asunto(s)
Artrogriposis/genética , Exoma , Familia , Artrogriposis/patología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , TurquíaRESUMEN
OBJECTIVES: Our aim was to evaluate ultrasound findings and perinatal outcome after prenatal diagnosis of lymphangioma. METHODS: This was a retrospective case series study. We searched the archives of our ultrasound database at our center for cases with the prenatal diagnosis of the lymphangioma in the period between January 2008 and November 2014. We described maternal, fetal and perinatal variables for all cases. RESULTS: Nine fetuses with lymphangioma were identified. All cases were diagnosed during the second and third trimesters with the average gestational age of 22.6 ± 3.9 weeks. The average diameter of lymphangioma was 55.4 ± 20.1 mm at the time of diagnosis. Five fetuses (55.6%) had lymphangioma on the neck, and four fetuses (44.4%) had lymphangioma on other localizations. Normal fetal karyotype was detected in all cases. There were a total of six live births, one intrauterine death and two medical terminations of pregnancy following the diagnosis of lymphangioma. No abnormal Doppler finding or hydrops were detected in the antenatal follow-up of remaining six cases. CONCLUSION: The risk of chromosomal abnormalities is very low in pregnancies with isolated lymphangioma. The outcome of pregnancies with lymphangioma is generally favorable and prognosis depends on their locations and size.
Asunto(s)
Aberraciones Cromosómicas , Enfermedades Fetales/diagnóstico por imagen , Linfangioma/diagnóstico por imagen , Adulto , Femenino , Enfermedades Fetales/genética , Humanos , Linfangioma/genética , Masculino , Embarazo , Estudios Retrospectivos , Ultrasonografía Prenatal , Adulto JovenRESUMEN
Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.
Asunto(s)
Encéfalo/patología , Redes Reguladoras de Genes/genética , Variación Genética/genética , Análisis de la Aleatorización Mendeliana/métodos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Encéfalo/anomalías , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , LinajeRESUMEN
We assessed DNA damage in patients with metabolic syndrome (MetS) by performing comet and micronucleus (MN) assays on peripheral blood lymphocyte cultures from study participants. 52 MetS patients and 35 age-matched healthy controls were evaluated for abdominal obesity, body-mass index (BMI), blood pressure, serum triglycerides, HbA1c, HDL-C, and fasting blood glucose levels. In addition, malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined. Serum levels of triglycerides, HbA1c, fasting blood glucose and waist circumference, systolic blood pressure, diastolic blood pressure, and BMI of the subjects in the MetS group were significantly higher than those of the control group (for each, p<0.001). However, the mean level of HDL-C in the MetS group was lower than in the control group (p<0.001). In the study, the length of comet tails was significantly higher in the MetS patients (10.23±1.98, range 5.72-15.08) than in the controls (3.12±1.73, range 0.6-7.1) (p<0.001). MN frequency was also significantly increased in MetS patients (3.68±1.27 per 1000 cells) compared to that of the control group (1.81±0.84 per 1000 cells) (p<0.001). Micronucleated cell frequency and comet-tail length in subjects showed positive correlations with waist circumference, BMI, and plasma triglyceride levels (p<0.01) and negative correlations with HDL-C levels (p<0.01). Among the oxidative stress factors, MDA levels were significantly higher in MetS patients than in the controls. However, SOD and GSH-Px enzyme activities were significantly lower in the MetS group than in the controls. These findings suggest that patients with MetS have increased DNA damage and oxidative stress.
Asunto(s)
Daño del ADN , Linfocitos/metabolismo , Síndrome Metabólico/genética , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/metabolismo , Presión Sanguínea , Índice de Masa Corporal , HDL-Colesterol/sangre , Ensayo Cometa , Femenino , Glutatión Peroxidasa/sangre , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Malondialdehído/sangre , Síndrome Metabólico/sangre , Síndrome Metabólico/patología , Síndrome Metabólico/fisiopatología , Pruebas de Micronúcleos , Persona de Mediana Edad , Obesidad Abdominal , Superóxido Dismutasa/sangre , Triglicéridos/sangre , Adulto JovenRESUMEN
Oral-facial-digital syndrome type VI (OFDVI) is a rare ciliopathy in the spectrum of Joubert syndrome (JS) and distinguished from other oral-facial-digital syndromes by metacarpal abnormalities with central polydactyly and by a molar tooth sign on cranial MRI. Additional characteristic features include short stature, micrognathia, posteriorly rotated low-set ears, hypertelorism, epicanthal folds, broad nasal tip, tongue hamartoma, upper lip notch, intraoral frenula, cleft lip/palate, and renal anomalies. Recently, novel mutations in C5orf42 were identified in 9 out of 11 OFDVI families. In a subsequent study C5orf42 was found to be mutated in only 2 out of 17 OFDVI probands while 28 patients with a pure JS phenotype also had pathogenic mutations of C5orf42. We report on two affected cousins diagnosed with OFDVI who were born from first degree cousin marriages. Whole exome sequencing (WES) identified a homozygous predicted damaging missense mutation (c.4034A > G; p.Gln1345Arg) in the C5orf42 gene. Our data contribute to the evidence that C5orf42 is one of the causative genes for OFDVI.
Asunto(s)
Exoma/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de la Membrana/genética , Mutación/genética , Síndromes Orofaciodigitales/genética , Anomalías Múltiples/genética , Enfermedades Cerebelosas/genética , Cerebelo/anomalías , Niño , Fisura del Paladar/genética , Anomalías del Ojo/genética , Femenino , Hamartoma/genética , Homocigoto , Humanos , Enfermedades Renales Quísticas/genética , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Fenotipo , Retina/anomalías , TurquíaRESUMEN
Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
Asunto(s)
Codón sin Sentido , Síndrome de Cornelia de Lange , Exoma , Regulación de la Expresión Génica , Fenotipo , Transcriptoma , Adolescente , Adulto , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Niño , Preescolar , Proteoglicanos Tipo Condroitín Sulfato/biosíntesis , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteínas Cromosómicas no Histona/biosíntesis , Proteínas Cromosómicas no Histona/genética , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Síndrome de Cornelia de Lange/patología , Exonucleasas , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Heterocigoto , Histona Desacetilasas/biosíntesis , Histona Desacetilasas/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Proteína de la Leucemia Mieloide-Linfoide/biosíntesis , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/genéticaRESUMEN
46,XY complete gonadal dysgenesis (Swyer syndrome) is a rare cause of disorder of sexual development. This syndrome is caused by a defect in the determination of sex during embryogenesis and is characterised with female external genitalia, normal or rudimentary uterus, and streak gonads, despite the presence of the 46,XY karyotype. Most of the studied cases presented with leak of secondary sex characteristics and primary amenorrhea during adolescence. Laboratory findings reveal hypergonadotropic hypogonadism. Herein we present the case of a female with a 46,XY karyotype who was admitted with delayed puberty and detected to have a microdeletion in the SRY gene and diagnosed to have Swyer syndrome. We highlight the importance of karyotype analysis in patients with delayed puberty and primary amenorrhea. Once the diagnosis of 46,XY complete gonadal dysgenesis is established, early laparoscopic removal of the dysgenetic gonads is crucial to prevent the development of gonadal malignancy.
Asunto(s)
Eliminación de Gen , Disgenesia Gonadal 46 XY/genética , Proteína de la Región Y Determinante del Sexo/genética , Adolescente , Castración , Femenino , Disgenesia Gonadal 46 XY/cirugía , Humanos , Pubertad Tardía/genética , Pubertad Tardía/cirugía , Cirugía de Reasignación de SexoRESUMEN
Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM#213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM#614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD.
Asunto(s)
Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Anomalías Múltiples/diagnóstico , Canales de Calcio , Exoma , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Masculino , Mutación , Isoformas de Proteínas/genéticaRESUMEN
Dyggve-Melchior-Clausen syndrome (DMC) (MIM #223800) is a rare autosomal-recessive type of skeletal dysplasia accompanied by variable degrees of intellectual disability (ID). It is characterized by progressive spondyloepimetaphyseal dysplasia leading to disproportionate short stature, microcephaly, and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic in this syndrome. The disorder results from mutations in the dymeclin (DYM) mapped to the 18q12-12.1 chromosomal region. Here, we report two cases with DMC: one with disproportionate short stature, developmental delay, and severe ID with a novel frameshift mutation (c.1028_1056del29) leading to a premature stop codon, and the second patient with classical clinical and radiological features of DMC with mild ID and rectal prolapse, which is very rare. The clinical diagnosis was confirmed with molecular analysis of DYM with a known mutation at c.580C>T (p.R194X). The parents and sibling of the second patient were heterozygous carriers with mild skeletal changes and short stature.
Asunto(s)
Discapacidades del Desarrollo/genética , Enanismo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Osteocondrodisplasias/congénito , Proteínas/genética , Niño , Preescolar , Codón sin Sentido/genética , Discapacidades del Desarrollo/patología , Enanismo/patología , Femenino , Mutación del Sistema de Lectura , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Lactante , Discapacidad Intelectual/patología , Péptidos y Proteínas de Señalización Intracelular , Microcefalia/complicaciones , Microcefalia/genética , Microcefalia/patología , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologíaRESUMEN
OBJECTIVE: We aimed to determine the prevalences of important genetic causes of thromboembolism for the first time in the western Black Sea Region of Turkey. PATIENTS AND METHODS: One hundred and eighty-eight patients diagnosed early with thrombophilia were included in the study. The samples were genotyped using real-time LightCycler. RESULTS: Of the 188 patients, 179 (95.2%) had one or more mutations. The frequencies of Factor V (FV) Leiden (FVL, G1691A), FV H1299R (A1299G), Factor II (FII G20210A), methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were 11.7%, 5.6%, 2.5%, 30.4% and 39.1%, respectively. FV1691A was commonly represented in deep venous thrombosis (34.2%). The highest frequencies of FV1299G and FII20210A were in the vascular headache and deep venous thrombosis groups (10% and 10.5%, respectively). MTHFR677T was common in the pulmonary embolism (37%). MTHFR1298C frequency was 55.9% in recurrent abortus. Within-group comparisons yielded significant differences in the distributions of the FVL and FV H1299R mutations (p=0.002 and p=0.039, respectively). CONCLUSION: There were significant positive associations between venous thromboembolism and FVL and FV H1299R. FVL mutation in DVT may be an important predisposing factor that needs to be tested routinely in this population.