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1.
Int J Methods Psychiatr Res ; 33(1): e2015, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38363207

RESUMEN

OBJECTIVES: This study validated the Japanese version of the Attention-Deficit/Hyperactivity Disorder-Rating Scale-5 (ADHD-RS-5) and the Disruptive Behavior Disorders Rating Scale. We extended the ADHD-RS-5 by adding the oppositional defiant disorder and conduct disorder subscales to compare the two rating scales psychometrically. METHODS: We examined the internal consistency, test-retest reliability, construct validity and criterion validity of the two rating scales in 135 Japanese outpatients aged 6-18 years. RESULTS: The internal consistency and test-retest reliability were good for all the subscales of the two rating scales except for the conduct disorder subscale of the ADHD-RS-5 extended. Good construct validity was revealed by expected correlational patterns between subscales from the two rating scales and the Children Behavior Checklist. The criterion validity was good for all the subscales of the two rating scales rated by parents, while teacher-ratings revealed substantially lower predictive ability for all the subscales. Agreement between parent- and teacher-ratings of the two rating scales was generally moderate and using predictive ratings alone of both ratings showed the best predictive ability among the integration methods examined. CONCLUSION: The two rating scales have sound psychometric properties and will aid in screening and severity assessment of externalizing disorders in Japanese clinical settings.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Problema de Conducta , Niño , Humanos , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Psicometría/métodos , Reproducibilidad de los Resultados , Japón , Pacientes Ambulatorios , Escalas de Valoración Psiquiátrica
2.
Eur J Hum Genet ; 2023 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-36973392

RESUMEN

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

3.
Clin Genet ; 103(5): 590-595, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36576140

RESUMEN

AFF3 at 2q11.2 encodes the nuclear transcriptional activator AF4/FMR2 Family Member 3. AFF3 constitutes super elongation complex like 3, which plays a role in promoting the expression of genes involved in neurogenesis and development. The degron motif in AFF3 with nine highly conserved amino acids is recognized by E3 ubiquitin ligase to induce protein degradation. Recently, AFF3 missense variants in this region and variants featuring deletion including this region were identified and shown to cause KINSSHIP syndrome. In this study, we identified two novel and one previously reported missense variants in the degron of AFF3 in three unrelated Japanese patients. Notably, two of these three variants exhibited mosaicism in the examined tissues. This study suggests that mosaic variants also cause KINSSHIP syndrome, showing various phenotypes.


Asunto(s)
Células Germinativas , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Fenotipo , Proteínas Nucleares
5.
Brain Dev ; 44(8): 578-582, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35527075

RESUMEN

INTRODUCTION: Bicaudal D homolog 2 (BICD2) is a causative gene of autosomal-dominant lower extremity-predominant spinal muscular atrophy-2 (SMA-LED2). The severity of SMA-LED2 varies widely, ranging from cases in which patients are able to walk to cases in which severe joint contractures lead to respiratory failure. In this study, we report the long-term course of a case of SMA-LED2 in comparison with previous reports. CASE REPORT: The patient was a 19-year-old woman. She had knee and hip dislocations with contractures, femoral fracture, and talipes calcaneovalgus since birth, and was diagnosed with arthrogryposis multiplex congenita. Intense respiratory support was not needed during the neonatal period. She had aspiration pneumonia repeatedly, necessitating NICU admission until 8 months of age. She achieved head control at 9 months of age and was able to sit at 2 years of age; however, she could not walk. Tube feeding was required until 3 years of age. At present, she can eat orally, move around with a wheelchair, and write words by herself. She needs non-invasive positive pressure ventilation during sleep because of a restrictive respiratory disorder during adolescence. Exome analysis identified a de novo heterozygous missense variant (c.2320G>A; p.Glu774Lys) in BICD2. CONCLUSION: Patients with SMA-LED2 may have a relatively better prognosis in terms of social activities in comparison with the dysfunction in the neonatal period. Moreover, it is important to periodically evaluate respiratory function in patients with SMA-LED2 because respiratory dysfunction may occur during adolescence.


Asunto(s)
Contractura , Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Adolescente , Adulto , Femenino , Humanos , Recién Nacido , Adulto Joven , Estudios de Seguimiento , Extremidad Inferior , Proteínas Asociadas a Microtúbulos/genética , Atrofia Muscular , Atrofia Muscular Espinal/genética , Mutación
6.
J Autism Dev Disord ; 52(5): 2149-2155, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34081298

RESUMEN

In March 2020, many schools were closed to prevent the spread of COVID-19 in Japan, and it is predicted that many children, especially those with neurodevelopmental disorders (NDDs), will be affected emotionally and behaviorally. Here, we examined the impact of school closures due to COVID-19 on school-aged children with NDDs using the Child Behavior Checklist. Totally, data on 121 children diagnosed with autism spectrum disorder, attention-deficit hyperactivity disorder, and/or intellectual disorder were analyzed and it was found that externalizing and aggressive behavior increased in all NDDs, regardless of the type of diagnosis. A clear prospect is important for children with NDDs children to lead a stable life, and more generous supports for children with NDDs and their families are needed.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , COVID-19 , Trastornos del Neurodesarrollo , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/psicología , COVID-19/prevención & control , Niño , Humanos , Japón/epidemiología , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/psicología
7.
Am J Ophthalmol Case Rep ; 24: 101230, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34825110

RESUMEN

PURPOSE: To report family members with familial retinal arteriolar tortuosity (FRAT) identified after sudden visual loss. OBSERVATIONS: A 15-year-old boy had sudden visual loss in his left eye while playing on a horizontal bar. He was referred to Nagoya City University Hospital from an eye clinic. The ophthalmologic examination showed retinal hemorrhage bilaterally. His best-corrected visual acuity (BCVA) was 20/17 in the right eye and 20/67 in the left eye. Bilateral retinal arteriolar tortuosity as well as retinal hemorrhage was seen. Since his mother with 54 years of age also had a history of retinal hemorrhage that improved spontaneously, fundus examination was performed, revealing tortuosity of the retinal arterioles. Consequently, the patient and his mother were diagnosed as FRAT. He was followed without intervention. Retinal hemorrhage gradually decreased and resolved after 3 months. The BCVA of his left eye gradually improved and reached 20/20 after 1 year. CONCLUSIONS AND IMPORTANCE: In this case, the family history was very useful for early diagnosis. Immediate and accurate diagnosis allowed the patient to be followed without intervention and achieve subsequent resolution of retinal hemorrhage and improved vision. FRAT should be considered in cases of sub-internal limiting membrane hemorrhages in young patients even in the presence of discrete retinal arteriolar tortuosity.

8.
J Autism Dev Disord ; 51(12): 4655-4662, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33590427

RESUMEN

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.


Asunto(s)
Trastorno del Espectro Autista , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genómica , Humanos
9.
Brain Dev ; 43(4): 590-595, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33402283

RESUMEN

INTRODUCTION: Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date. CASE REPORT: The case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant. CONCLUSION: Here, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system.


Asunto(s)
Codón sin Sentido , Citocinas/genética , Discapacidades del Desarrollo/genética , Leucoencefalopatías/genética , Espasticidad Muscular/genética , Proteínas de Neoplasias/genética , Nervios Periféricos/fisiopatología , Proteínas de Unión al ARN/genética , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/fisiopatología , Humanos , Lactante , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/fisiopatología , Imagen por Resonancia Magnética , Masculino , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/fisiopatología , Conducción Nerviosa/fisiología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/fisiopatología
10.
Epilepsy Behav ; 111: 107321, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32698109

RESUMEN

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported. AIM: The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment. METHOD: The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale-2nd edition (SRS-2). RESULTS: All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; P = 0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (P = 0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score. CONCLUSION: Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest "TAND impact" on families.


Asunto(s)
Relaciones Familiares/psicología , Problema de Conducta/psicología , Distrés Psicológico , Esclerosis Tuberosa/psicología , Adolescente , Anticonvulsivantes/uso terapéutico , Lista de Verificación/métodos , Niño , Preescolar , Femenino , Humanos , Masculino , Anamnesis/métodos , Convulsiones/tratamiento farmacológico , Convulsiones/psicología , Esclerosis Tuberosa/tratamiento farmacológico , Vigabatrin/uso terapéutico
11.
Hum Genome Var ; 6: 43, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31645981

RESUMEN

Patients with variants in CUL4B exhibit syndromic intellectual disability (MIM #300354). A seven-year-old boy presented with intellectual disability, a history of seizure, characteristic facial features, and short stature. Whole-exome sequencing detected a c.974+3A>G variant in CUL4B, which was subsequently confirmed to disrupt mRNA splicing. The current patient showed less pronounced phenotypic features compared with the previously reported cases. This report, therefore, provides evidence of genotype-phenotype correlations in CUL4B-related disorders.

12.
Hum Genome Var ; 6: 15, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30937176

RESUMEN

A loss of function mutation in SLC9A6 (Xq26.3) is responsible for Christianson syndrome in males. We identified a novel splicing mutation (NM_006359.2:c.1141-8C>A) of SLC9A6 in a seven-year-old boy with microcephaly, severe developmental delay, and intractable epilepsy. Functional analysis found multiple aberrant transcripts, none of which maintained the canonical open reading frame. Computer prediction tools, however, failed to detect all of the aberrant transcripts.

13.
J Hum Genet ; 64(7): 701-702, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31028281

RESUMEN

Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349-1358, 2016 https://doi.org/10.1038/ng.3676 ). Therefore the mutation is not novel but recurrent. Accordingly, the word "novel" should be deleted throughout the article including the title. Thus, the title should read "A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate."

14.
Brain Dev ; 40(8): 678-684, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29752200

RESUMEN

BACKGROUND: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. METHODS: PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. RESULTS: We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (-0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. CONCLUSION: The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.


Asunto(s)
Discapacidades del Desarrollo/genética , Cara/anomalías , Megalencefalia/genética , Mutación , Fosfohidrolasa PTEN/genética , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Femenino , Humanos , Masculino , Megalencefalia/diagnóstico por imagen , Fenotipo
15.
Physiol Meas ; 39(5): 054004, 2018 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-29693554

RESUMEN

OBJECTIVE: To adapt to a new environment or situation, biological systems explore the most convenient state while moving between attractors by the force of random fluctuation. From this concept, the random component in physiological signals is assumed to increase during developmental and degenerative stages of life. To examine this hypothesis, we measured the age-dependent changes in the random component of heart rate variability (HRV) in 24-h electrocardiography (ECG) big data and in patients with a developmental disorder (DD). APPROACH: We measured separately regulated and random components of HRV with autoregressive (AR) model fitting, by which the ratio of random component as the fractional variance of AR residual time series. From the ALLSTAR database of about 304 000 ambulatory 24-h ECGs, we randomly extracted the data of 1930 men and 1987 women uniformly for all ages from 0 to 100 years old (100 cases per 5-year strata for each sex). Data were also obtained from male pediatric patients with DD (age 10-15 years). MAIN RESULTS: While the variance of the regulated component of HRV increased from age 0 to 20, decreased with age until 40, and reached a plateau in both sexes, the ratio of the random component was high at birth, decreased with age until 35 in men and 30 in women, and increased again after 75 in men and 85 in women (P < 0.0001 for all). In patients with a DD, the ratio of the random component was significantly lower than that in age-and-sex matched subjects in the database. SIGNIFICANCE: We found that the ratio of the random component of HRV is increased during developmental and degenerative stages of life and that it may be reduced in DD patients during their development.


Asunto(s)
Envejecimiento/fisiología , Frecuencia Cardíaca , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Discapacidades del Desarrollo/fisiopatología , Electrocardiografía , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Adulto Joven
16.
Cell Rep ; 22(3): 734-747, 2018 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-29346770

RESUMEN

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.


Asunto(s)
Trastorno del Espectro Autista/genética , Mutación/genética , Trastorno del Espectro Autista/patología , Predisposición Genética a la Enfermedad , Humanos
17.
J Pediatr Endocrinol Metab ; 30(10): 1111-1118, 2017 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-28915117

RESUMEN

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n)CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH. METHODS: We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing. RESULTS: We detected 12 potentially pathogenic mutations in 11 families, with three having a mutation in ANOS1 (X-linked recessive); three and four having a mutation in FGFR1 and CHD7, respectively (autosomal dominant); and one having two TACR3 mutations (autosomal recessive). Among four patients with KS carrying a CHD7 mutation, one had perceptive deafness and two had a cleft lip/palate. CONCLUSIONS: The frequency of CHH genes in the Japanese was compatible with previous reports, except that CHD7 mutations might be more common. Furthermore, partial phenotype-genotype correlations were demonstrated in our cohort.


Asunto(s)
Hipogonadismo/diagnóstico , Síndrome de Kallmann/diagnóstico , Mutación , Adolescente , Niño , Preescolar , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Proteínas de la Matriz Extracelular/genética , Femenino , Humanos , Hipogonadismo/genética , Lactante , Síndrome de Kallmann/genética , Masculino , Proteínas del Tejido Nervioso/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adulto Joven
18.
J Med Genet ; 54(12): 836-842, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28848059

RESUMEN

BACKGROUND: Heterozygous mutations in CTCF have been reported in patients with distinct clinical features including intellectual disability. However, the precise pathomechanism underlying the phenotype remains to be uncovered, partly because of the diverse function of CTCF. Here we describe extensive clinical and genetic investigation for two patients with a microdeletion encompassing CTCF. METHODS: We performed genetic examination including comprehensive investigation of X chromosome inactivation and DNA methylation profiling at imprinted loci and genome-wide. RESULTS: Two patients showed comparable clinical features to those in a previous report, indicating that haploinsufficiency of CTCF was the major determinant of the microdeletion syndrome. Despite the haploinsufficiency of CTCF, X chromosome inactivation was normal. DNA methylation at imprinted loci was normal, but hypermethylation at CTCF binding sites was demonstrated, of which PRKCZ and FGFR2 were identified as candidate genes. CONCLUSIONS: This study confirms that haploinsufficiency of CTCF causes distinct clinical features, and that a microdeletion encompassing CTCF could cause a recognisable CTCF deletion syndrome. Perturbed DNA methylation at CTCF binding sites, not at imprinted loci, may underlie the pathomechanism of the syndrome.


Asunto(s)
Factor de Unión a CCCTC/genética , Eliminación de Gen , Estudios de Asociación Genética , Factor de Unión a CCCTC/metabolismo , Preescolar , Hibridación Genómica Comparativa , Metilación de ADN , Epigénesis Genética , Facies , Femenino , Haploinsuficiencia , Humanos , Hibridación Fluorescente in Situ , Fenotipo , Análisis de Secuencia de ADN , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Síndrome , Inactivación del Cromosoma X
19.
Acta Paediatr ; 106(11): 1817-1824, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28695677

RESUMEN

AIM: We evaluated combined genetic analyses with targeted next-generation sequencing (NGS), multiplex ligation probe amplification (MLPA) of Jagged1 (JAG1) genes and microarray comparative genomic hybridisation (CGH) in subjects with Alagille syndrome, incomplete clinical features of Alagille syndrome and biliary atresia. METHODS: Subjects recruited from April 2013 to December 2015 underwent a targeted NGS analysis, including JAG1 and Notch homolog 2 (NOTCH2). If no mutations were detected in JAG1 or NOTCH2, or if copy number variations were suggested by the NGS analysis, we performed an MLPA analysis of JAG1. We also performed a microarray CGH analysis with whole-exon deletion detected by the MLPA analysis. RESULTS: We analysed 30 subjects with Alagille syndrome, nine with incomplete Alagille syndrome and 17 with biliary atresia and detected pathogenic mutations in JAG1 or NOTCH2 in 24/30 subjects with Alagille syndrome and in 4/9 subjects with incomplete Alagille syndrome. No pathogenic mutations were detected in subjects with biliary atresia. The frequency of JAG1 mutations was as follows: single nucleotide variants (51.9%), small insertion or deletion (29.6%) and gross deletion (18.5%). CONCLUSION: Combined genetic analyses achieved efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome.


Asunto(s)
Síndrome de Alagille/diagnóstico , Pruebas Genéticas , Proteína Jagged-1/genética , Síndrome de Alagille/genética , Atresia Biliar/genética , Hibridación Genómica Comparativa , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa Multiplex
20.
J Hum Genet ; 62(9): 861-863, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28515470

RESUMEN

We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G>A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.


Asunto(s)
Fisura del Paladar/diagnóstico , Fisura del Paladar/genética , Mutación Missense , Ubiquitina-Proteína Ligasas Nedd4/genética , Heterotopia Nodular Periventricular/diagnóstico , Heterotopia Nodular Periventricular/genética , Polimicrogiria/diagnóstico , Polimicrogiria/genética , Encéfalo/anomalías , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Humanos , Imagen por Resonancia Magnética , Dominios Proteicos/genética
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