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1.
Am J Med Genet A ; 191(2): 400-407, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36345653

RESUMEN

Interstitial microdeletions in the long arm of chromosome 3 are rare. In this study, we identified two patients with approximately 5-Mb overlapping deletions in the 3q26.2q26.31 region. Both patients showed neurodevelopmental delays, congenital heart defects, and distinctive facial features. One of them showed growth deficiency and brain abnormalities, as shown on a magnetic resonance imaging scan. Haploinsufficiency of NLGN1 and FNDC3B present in the common deletion region was considered to be responsible for neurodevelopmental delay and the distinctive features, respectively. The possibility of unmasked variants in PLD1 was considered and analyzed, but no possible pathogenic variant was found, and the mechanism of the congenital heart defects observed in the patients is unknown. Because 3q26.2q26.31 deletions are rare, more information is required to establish genotype-phenotype correlations associated with microdeletions in this region.


Asunto(s)
Cardiopatías Congénitas , Malformaciones del Sistema Nervioso , Humanos , Deleción Cromosómica , Fenotipo , Cardiopatías Congénitas/genética , Malformaciones del Sistema Nervioso/genética
2.
Am J Med Genet A ; 191(1): 112-119, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36282026

RESUMEN

Most chromosomal aberrations revealed by chromosomal microarray testing (CMA) are simple; however, very complex chromosomal structural rearrangements can also be found. Although the mechanism of structural rearrangements has been gradually revealed, not all mechanisms have been elucidated. We analyzed the breakpoint-junctions (BJs) of two or more clustered copy number variations (CNVs) in the same chromosome arms to understand their conformation and the mechanism of complex structural rearrangements. Combining CMA with long-read whole-genome sequencing (WGS) analysis, we successfully determined all BJs for the clustered CNVs identified in four patients. Multiple CNVs were intricately intertwined with each other, and clustered CNVs in four patients were involved in global complex chromosomal rearrangements. The BJs of two clustered deletions identified in two patients showed microhomologies, and their characteristics were explained by chromothripsis. In contrast, the BJs in the other two patients, who showed clustered deletions and duplications, consisted of blunt-end and nontemplated insertions. These findings could be explained only by alternative nonhomologous end-joining, a mechanism related to polymerase theta. All the patients had at least one inverted segment. Three patients showed cryptic aberrations involving a disruption and a deletion/duplication, which were not detected by CMA but were first identified by WGS. This result suggested that complex rearrangements should be considered if clustered CNVs are observed in the same chromosome arms. Because CMA has potential limitations in genotype-phenotype correlation analysis, a more detailed analysis by whole genome examination is recommended in cases of suspected complex structural aberrations.


Asunto(s)
Variaciones en el Número de Copia de ADN , Genoma Humano , Humanos , Variaciones en el Número de Copia de ADN/genética , Reordenamiento Génico/genética , Aberraciones Cromosómicas , Análisis de Secuencia
3.
Hum Mutat ; 41(12): 2119-2127, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32906213

RESUMEN

Chromosomal triplications can be classified into recurrent and nonrecurrent triplications. Most of the nonrecurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern.


Asunto(s)
Rotura Cromosómica , Reordenamiento Génico/genética , Genoma Humano , Preescolar , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Femenino , Dosificación de Gen , Humanos , Lactante , Recién Nacido , Masculino , Secuenciación de Nanoporos
4.
Hum Genet ; 139(12): 1555-1563, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32535809

RESUMEN

The chromosomal region critical in Down syndrome has long been analyzed through genotype-phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syndrome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the short region and overlapped with repeated segments. The rearrangement resulted in a maximum gain of five copies, but no region showed loss of genomic copy numbers. Breakpoint-junctions showed no homologous region. Based on these findings, chromoanasynthesis was considered as the mechanism. Although the distal 21q22.13 region was not included in the aberrant regions, some of the genes located on the duplicated regions, SOD1, SON, ITSN1, RCAN1, and RUNX1, were considered as possible candidate genes for clinical features of the patient. We discussed the critical region for Down syndrome, with the literature review.


Asunto(s)
Cromosomas Humanos Par 21/genética , Cromosomas Humanos/genética , Síndrome de Down/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Aberraciones Cromosómicas , Hibridación Genómica Comparativa/métodos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/genética , Síndrome de Down/fisiopatología , Femenino , Dosificación de Gen/genética , Estudios de Asociación Genética , Humanos , Hibridación Fluorescente in Situ/métodos , Lactante , Análisis por Micromatrices/métodos , Antígenos de Histocompatibilidad Menor/genética , Proteínas Musculares/genética , Superóxido Dismutasa-1/genética , Secuenciación Completa del Genoma
5.
J Hum Genet ; 65(9): 735-741, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32355308

RESUMEN

The widespread use of genomic copy number analysis has revealed many previously unknown genomic structural variations, including some which are more complex. In this study, three consecutive microdeletions were identified in the same chromosome by microarray-based comparative genomic hybridization (aCGH) analysis for a patient with a neurodevelopmental disorder. Subsequent fluorescence in situ hybridization (FISH) analyses unexpectedly suggested complicated translocations and inversions. For better understanding of the mechanism, breakpoint junctions were analyzed by nanopore sequencing, as a new long-read whole-genome sequencing (WGS) tool. The results revealed a new chromosomal disruption, giving rise to four junctions in chromosome 7. According the sequencing results of breakpoint junctions, all junctions were considered as the consequence of multiple double-strand breaks and the reassembly of DNA fragments by nonhomologous end-joining, indicating chromothripsis. KMT2E, located within the deletion region, was considered as the gene responsible for the clinical features of the patient. Combinatory usage of aCGH and FISH analyses would be recommended for interpretation of structural variations analyzed through WGS.


Asunto(s)
Aberraciones Cromosómicas , Hibridación Genómica Comparativa/métodos , Proteínas de Unión al ADN/genética , Genómica/métodos , Hibridación Fluorescente in Situ/métodos , Trastornos del Neurodesarrollo/genética , Rotura Cromosómica , Inversión Cromosómica , Roturas del ADN de Doble Cadena , Variaciones en el Número de Copia de ADN , Reparación del ADN por Unión de Extremidades , Femenino , Estudios de Asociación Genética , Genoma Humano , Humanos , Secuenciación de Nanoporos , Análisis de Secuencia por Matrices de Oligonucleótidos , Inversión de Secuencia , Translocación Genética , Secuenciación Completa del Genoma , Adulto Joven
6.
Am J Med Genet A ; 182(3): 521-526, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31821719

RESUMEN

Primrose syndrome is a congenital malformation syndrome characterized by intellectual disability, developmental delay, progressive muscle wasting, and ear lobe calcification. Mutations in the ZBTB20 gene have been established as being accountable for this syndrome. In this study, a novel de novo ZBTB20 mutation, NM_001164342.2:c.1945C>T (p.Leu649Phe), has been identified through whole exome sequencing (WES) in a female patient presenting a typical Primrose phenotype. Because the present patient exhibited recurrent otitis media, detailed immunological examinations were performed in this study and subnormal immunoglobulin levels were firstly identified in a Primrose patient. Anatomical anomaly of the inner ear has never been reported in this patient and WES data did not include any relevant variants causally linked with the immunologic defect. Thus, there is a possibility of a relation between an unclassified immunodeficiency with selective IgG2 deficiency and Primrose syndrome and this may be the reason of recurrent otitis media frequently observed in Primrose patients. Because subnormal levels of IgG2 in this patient might be caused by an unrelated and still uncharacterized genetic cause, further studies are required to prove the causal link between aberrant ZBTB20 function and immunodeficiency.


Asunto(s)
Anomalías Múltiples/genética , Calcinosis/genética , Discapacidades del Desarrollo/genética , Enfermedades del Oído/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Atrofia Muscular/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/patología , Calcinosis/diagnóstico , Calcinosis/patología , Niño , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/patología , Enfermedades del Oído/diagnóstico , Enfermedades del Oído/patología , Femenino , Humanos , Inmunoglobulina G/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/patología , Mutación Missense/genética , Fenotipo , Secuenciación del Exoma
7.
J Hum Genet ; 64(7): 665-671, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31004103

RESUMEN

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5(PLP1_v001):c.783del; p.Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.


Asunto(s)
Mutación del Sistema de Lectura , Proteína Proteolipídica de la Mielina/genética , Paraplejía/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Alelos , Línea Celular , Niño , Cromosomas Humanos X/genética , Cromosomas Humanos X/metabolismo , Decitabina/farmacología , Femenino , Humanos , Enfermedad de Pelizaeus-Merzbacher/patología , Enfermedad de Pelizaeus-Merzbacher/terapia , Piperazinas/farmacología , Secuenciación del Exoma
8.
Am J Med Genet A ; 176(12): 2803-2807, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30152144

RESUMEN

Vici syndrome is a rare, autosomal recessive, multisystem disorder, characterized by agenesis of the corpus callosum, cataracts, psychomotor delay, cardiomyopathy, hypopigmentation, and recurrent infections. Mutations in the ectopic P-granules autophagy protein 5 homolog gene (EPG5), which encodes a key autophagy regulator, are responsible for this syndrome. A 3-year-old Japanese girl manifesting similar symptoms to those found in patients with Vici syndrome showed intractable diarrhea, rather than immunodeficiency. Whole exome sequencing identified only a heterozygous variant in EPG5, NM_020964.2(EPG5):c.3389A > C (p.His1130Pro), which was inherited from her mother. Sequencing analyses of the EPG5 messenger RNA showed only an altered nucleotide "C" at position, c.3389, indicating decreased expression of the wild-type allele. Microarray-based comparative genomic hybridization revealed a de novo microduplication in the exon 1 region. Large exon deletions and duplications of EPG5 have never been reported so far. This was considered the cause of the decreased expression of the wild-type allele. In conclusion, we successfully identified novel compound heterozygous mutations in EPG5 in a patient who was clinically considered to have Vici syndrome.


Asunto(s)
Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/genética , Catarata/diagnóstico , Catarata/genética , Exones , Duplicación de Gen , Heterocigoto , Proteínas de Membrana de los Lisosomas/genética , Mutación , Proteínas de Transporte Vesicular/genética , Proteínas Relacionadas con la Autofagia , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Preescolar , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Genómica/métodos , Humanos , Japón , Imagen por Resonancia Magnética , Fenotipo
9.
Congenit Anom (Kyoto) ; 61(2): 63-67, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33244819

RESUMEN

Large deletions in Xq22 are responsible for neurodevelopmental disorders, including severe intellectual disability and behavioral abnormalities. Although the deletion regions contain PLP1, the gene related to Pelizaeus-Merzbacher disease (PMD), patients with Xq22 deletions show no clinical features of PMD such as paraplegia and white matter abnormalities. This could be due to skewed X-chromosome inactivation (XCI) occurring predominantly in the affected allele. Isogenic pairs of wild type and mutant induced pluripotent stem cells (iPSCs) were established from the patient. In the iPSC line in which the wild type allele was inactivated, PLP1 was not expressed, but biallelic expression of BEX2 was identified. This suggests that BEX2 escaped from XCI and haploinsufficiency of BEX2 may be related to the phenotype of Xq22 deletions.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22 , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas del Tejido Nervioso/genética , Inactivación del Cromosoma X , Alelos , Femenino , Estudios de Asociación Genética , Humanos , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
10.
Hum Genome Var ; 8(1): 14, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795668

RESUMEN

Recently, altered PLP1 splicing was confirmed as a genetic cause of hypomyelination of early myelinating structures (HEMS). A novel deep intronic deletion in intron 3 of PLP1 (NM_000533.5: c.453+59_+259del) was identified, and an in vitro minigene assay detected abnormal splicing patterns. However, the clinical and radiological findings of the patient were compatible with a severe phenotype of Pelizaeus-Merzbacher disease rather than HEMS, which may be due to undetected abnormal PLP1 splicing.

11.
Hum Genome Var ; 8(1): 16, 2021 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-33958584

RESUMEN

A recurrent ZSWIM6 variant, NM_020928.2:c.2737C>T [p.Arg913*], was identified in a Japanese male patient with severe neurodevelopmental delay, epilepsy, distinctive facial features, microcephaly, growth deficiency, abnormal behavior, and frequent vomiting but without frontonasal or limb malformations. In this patient, distinctive facial features gradually became apparent with age, and severe vomiting caused by gastroesophageal reflux continued even after percutaneous endoscopic gastrostomy.

12.
Congenit Anom (Kyoto) ; 60(1): 10-14, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30684281

RESUMEN

Genomic copy number variations (CNVs) can be detected by chromosomal microarray testing. However, upon final diagnosis, other methods may be recommended for a validation method to confirm CNVs. Trio analyses or carrier detection in family members are also frequently required. Previously, fluorescence in situ hybridization and/or quantitative PCR have been used; however, these methods present limitations. The purpose of this study was to establish a simple and rapid method to detect genomic copy numbers. We utilized droplet digital PCR (dPCR) with an intercalation method. Thirteen patients, who were diagnosed with MECP2 duplications via chromosomal microarray testing, were enrolled in this study. Four of their female relatives, who were verified as carriers of MECP2 duplications, were also included. Genomic copy numbers of MECP2 and IRAK1 were analyzed in comparison with reference genes: XIST and AR on the X-chromosome, and RPP30 and RPPH1 on the autosomal chromosomes. As a result, genomic copy numbers of MECP2 were rapidly and precisely detected by the dPCR system established in this study. This method can be widely applied as a diagnostic method to confirm CNVs on other chromosomal regions.


Asunto(s)
Duplicación de Gen/genética , Quinasas Asociadas a Receptores de Interleucina-1/genética , Proteína 2 de Unión a Metil-CpG/genética , Reacción en Cadena de la Polimerasa/métodos , Autoantígenos/genética , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN/genética , Femenino , Genoma/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Proteína 2 de Unión a Metil-CpG/aislamiento & purificación , Análisis por Micromatrices , Linaje , ARN Largo no Codificante/genética , Receptores Androgénicos/genética , Ribonucleasa P/genética
13.
Hum Genome Var ; 7: 16, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32509318

RESUMEN

Comprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.

14.
Anticancer Res ; 40(8): 4567-4570, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32727787

RESUMEN

BACKGROUND/AIM: Historically, breast cancer has been treated according to an evaluation of biomarkers, such as the estrogen receptor and HER2 status. Recently, molecular profiling has been used to detect driver mutations and select anti-cancer treatment strategies. In addition to detecting pathogenic mutations, the total mutation count (tumor mutation burden) has been considered as another biomarker. MATERIALS AND METHODS: We performed molecular profiling of 143 breast cancer tissues obtained from resected tissues via surgical operation. RESULTS: Suspected germline mutations were detected in 10% of the patients with a higher somatic mutation ratio. CONCLUSION: As hypermutated breast cancers are more likely to benefit from certain anti-cancer treatment strategies, molecular profiling can be used as a biomarker.


Asunto(s)
Neoplasias de la Mama/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Mutación de Línea Germinal/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Persona de Mediana Edad , Receptor ErbB-2/genética , Receptores de Estrógenos/genética
15.
Hum Genome Var ; 7(1): 42, 2020 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-33298904

RESUMEN

Genetic causes of undiagnosed hemolytic anemia in nineteen patients were analyzed by whole-exome sequencing, and novel COL4A1 variants were identified in four patients (21%). All patients were complicated with congenital malformations of the brain, such as porencephaly or schizencephaly. In these patients, hemolysis became less severe within 2 months after birth, and red cell transfusion was no longer required after 50 days, whereas chronic hemolysis continued.

16.
Intractable Rare Dis Res ; 8(3): 198-202, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31523598

RESUMEN

Pelizaeus-Merzbacher disease (PMD) is an X-linked, recessively inherited disorder associated with hypomyelination in the brain white matter. Mutations involving the proteolipid protein 1 gene (PLP1) located on Xq22.2 are responsible for PMD. PLP1 duplication is the major genetic abnormality in PMD patients. In this study, we utilized droplet-digital polymerase chain reaction (ddPCR) as a potential method to detect PLP1 duplications. Samples from four PMD patients and one of their mothers were used as positive controls. They had been previously diagnosed as having an additional PLP1 copy by chromosomal microarray testing. Genomic copy number of PLP1 was analyzed in triplicate experiments and compared with reference genes XIST and AR on the X-chromosome, and RPP30 and RPPH1 on the autosomes. As a result, precise results were obtained for each triplicate procedure. Thus, we concluded that triplicate experiments are no longer necessary. Compared to other methods, including fluorescence in-situ hybridization, multiplex ligation-dependent probe amplification, chromosomal microarray testing, and quantitative PCR, we were able to establish ddPCR results rapidly with very small amounts of DNA. In conclusion, we showed that ddPCR can be a potential diagnostic tool to confirm genomic copy number as a routine clinical application, including in prenatal diagnostic settings.

17.
Brain Dev ; 41(3): 257-262, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30424912

RESUMEN

BACKGROUND: FOXP1 is known as the gene responsible for neurodevelopmental delay associated with language impairment. Broad clinical findings also include feeding difficulty, muscular hypotonia, and distinctive features. These findings are common between patients with loss-of-function mutations in FOXP1 and 3p13 microdeletion involving FOXP1. Thus, "FOXP1-related intellectual disability syndrome" is now recommended. METHODS: After obtaining informed consent, chromosomal microarray testing was performed for patients with unknown etiology. RESULTS: We identified three Japanese patients with 3p13 microdeletions involving FOXP1. One of the patients showed an additional 1q31.3q32.1 deletion as de novo, which was rather considered as a benign copy number variant. CONCLUSION: This is the first report of patients with 3p13 microdeletions from Japan. All patients showed growth delay, moderate to severe developmental delay, hearing loss, and distinctive facial features including prominent forehead and mid facial hypoplasia. In addition, "square shaped face" commonly observed in all three patients may be a characteristic finding undescribed previously. From the obtained findings, "FOXP1-related intellectual disability syndrome" was considered to be clinically recognizable.


Asunto(s)
Deleción Cromosómica , Discapacidades del Desarrollo/genética , Factores de Transcripción Forkhead/genética , Trastornos del Lenguaje/genética , Mutación/genética , Proteínas Represoras/genética , Pueblo Asiatico , Niño , Preescolar , Cromosomas Humanos Par 3/genética , Discapacidades del Desarrollo/complicaciones , Femenino , Humanos , Lactante , Trastornos del Lenguaje/complicaciones , Masculino , Análisis por Micromatrices
18.
Congenit Anom (Kyoto) ; 59(5): 169-173, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30378700

RESUMEN

Wolf-Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype-phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause "typical WHS facial appearance". In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted-duplication-deletion. Among 10 patients, one patient did not show "typical WHS facial appearance" although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited "typical WHS facial appearance" although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.


Asunto(s)
Aberraciones Cromosómicas , Estudios de Asociación Genética , Fenotipo , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/genética , Adolescente , Adulto , Niño , Preescolar , Mapeo Cromosómico , Facies , Femenino , Estudios de Asociación Genética/métodos , Humanos , Lactante , Recién Nacido , Masculino , Adulto Joven
19.
Brain Dev ; 41(5): 452-455, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30635136

RESUMEN

1q41q42 microdeletion syndrome has been established in 2007. Since then, more than 17 patients have been reported so far. The reported deletions showed random breakpoints and deletion regions are aligned as roof tiles. Patients with 1q41q42 microdeletion syndrome show intellectual disability, seizures, and distinctive features. Many genotype-phenotype correlation studies have been performed and some genes included in this region have been suggested as potential candidate genes. Recently, de novo variants in WDR26 and FBXO28 were identified in patients who showed consistent phenotypes with 1q41q42 microdeletion syndrome. Thus, both genes are now considered as the genes possibly responsible for 1q41q42 microdeletion syndrome. Here, the first case of a Japanese patient with a de novo 1q41q42 microdeletion is reported. Owing to the distinctive features, this syndrome would be clinically recognizable.


Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/fisiopatología , Cromosomas Humanos Par 1/genética , Trastornos Neurológicos de la Marcha/genética , Discapacidad Intelectual/genética , Proteínas/genética , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Adaptadoras Transductoras de Señales , Niño , Femenino , Humanos , Japón , Fenotipo , Síndrome
20.
Brain Dev ; 41(9): 776-782, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31171384

RESUMEN

BACKGROUND: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders. METHODS: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM). RESULTS: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1. CONCLUSION: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.


Asunto(s)
Trastornos del Neurodesarrollo/genética , Pueblo Asiatico/genética , Preescolar , Variaciones en el Número de Copia de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Japón , Masculino , Polimorfismo de Nucleótido Simple
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