Jye-Siung Fang

Identification and molecular characterization of two novel chromosomal deletions associated with autism.

Chien W‐H, Gau SS‐F, Wu Y‐Y, Huang Y‐S, Fang J‐S, Chen Y‐J, Soong W‐T, Chiu Y‐N, Chen C‐H. Identification and molecular characterization of two novel chromosomal deletions associated with autism.

Identification and characterization of three inherited genomic copy number variations associated with familial schizophrenia

Schizophrenia is a complex mental disorder with high degree of genetic influence in its etiology. Several recent studies revealed that copy number variations (CNVs) of genomic DNA contributed significantly to the genetic architecture of sporadic schizophrenia. This study aimed to investigate whether CNVs also contribute to the familial forms of schizophrenia. Using array-based comparative genomic hybridization technology, we searched for pathogenic CNV associated with schizophrenia in a sample of 60 index cases from multiplex schizophrenia families. We detected three inherited CNVs that were associated with schizophrenia in three families, including a microdeletion of ~4.4Mb at chromosome 6q12-q13, a microduplication of ~1Mb at chromosome 18q12.3, and an interstitial duplication of ~5Mb at chromosome 15q11.2-q13.1. Our data indicate that CNVs contribute to the genetic underpinnings of the familial forms of schizophrenia as well as of the sporadic form. As 15q11-13 duplication is a well-known recurrent CNV associated with autism in the literature, the detection of the 15q11.2-q13.1 duplication in our schizophrenia patients provides additional support to other studies reporting that schizophrenia is part of the clinical spectrum of 15q11-q13 duplication syndrome.

A novel microdeletion at chromosome 2q31.1-31.2 in a three-generation family presenting duplication of great toes with clinodactyly

HOXD gene cluster maps to chromosome 2q31 and plays a key role in embryonic limb morphogenesis. Mutations of the HOXD13 and HOXD10 genes have been found to be associated with digital and limb malformations. In addition, dysregulation of HOXD gene cluster has been proposed to account for the limb abnormalities in patients with chromosome 2q rearrangements. In this report, we investigated a three‐generation family presenting clinical phenotypes of duplication of great toes, tapering fingers, and clinodactyly of the fifth finger in both hands, which were transmitted in a dominant fashion in this family. We identified and validated an interstitial microdeletion of ∼3.4 Mb at chromosome 2q31.1‐31.2 by array‐based comparative genomic hybridization, fluorescence in situ hybridization, and real‐time quantitative polymerase chain reaction that cosegregates with the clinical phenotypes in this family. The microdeletion removes 30 labeled genes including the entire HOXD gene cluster, suggesting that the digital abnormalities of this family may be attributed to the haploinsufficiency of the HOXD gene cluster. The delineation of the microdeletion region may contribute to the genotype–phenotype correlation study in patients with genomic rearrangements of the long arm of chromosome 2 and helps to understand the pathogenesis of haploinsufficiency of the HOXD gene cluster.

Cytogenetic and molecular characterization of a three-generation family with chromosome 5p terminal deletion

Terminal or interstitial deletion on the short arm of chromosome 5 is associated with a genetic disorder, cri‐du‐chat syndrome (cat cry syndrome), which is characterized by a cat‐like cry in infancy, facial dysmorphism, microcephaly, and mental retardation. There is a high degree of variation in clinical presentations of patients with cri‐du‐chat syndrome, which is usually associated with different sizes and locations of deletions in chromosome 5p. Most patients with a 5p deletion have de novo mutations; familial 5p deletion is rare in literature. Here, we report a three‐generation family with a 5p terminal deletion. The terminal 5p deletion (5p15.2‐pter) in this family was confirmed and characterized by karyotyping analysis, fluorescent in situ hybridization, array comparative genome hybridization, and quantitative polymerase chain reaction. Although the affected family members apparently share deletions of the same size, there are some variations in mental symptoms within this family. Two affected females manifest moderate mental retardation and psychotic symptoms such as delusion of persecution, auditory hallucination, self‐talking, and self‐laughing, which are rare in cri‐du‐chat syndrome. In contrast, the other three affected males express mild‐to‐moderate mental retardation but no psychotic symptoms. Our study suggests that other factors besides the size and location of 5p deletions may modify the mental presentations of patients with 5p deletions.

Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan.

Autism spectrum disorders (ASD) are childhood‐onset neurodevelopmental disorders characterized by verbal communication impairments, social reciprocity deficits, and the presence of restricted interests and stereotyped behaviors. Genetic factors contribute to the incidence of ASD evidently. However, the genetic spectrum of ASD is highly heterogeneous. Chromosomal abnormalities contribute significantly to the genetic deficits of syndromic and non‐syndromic ASD. In this study, we conducted karyotyping analysis in a sample of 500 patients (447 males, 53 females) with ASD from Taiwan, the largest cohort in Asia, to the best of our knowledge. We found three patients having sex chromosome aneuploidy, including two cases of 47, XXY and one case of 47, XYY. In addition, we detected a novel reciprocal chromosomal translocation between long arms of chromosomes 4 and 14, designated t(4;14)(q31.3;q24.1), in a patient with Aspergers disorder. This translocation was inherited from his unaffected father, suggesting it might not be pathogenic or it needs further hits to become pathogenic. In line with other studies, our study revealed that subjects with sex chromosomal aneuploidy are liable to neurodevelopmental disorders, including ASD, and conventional karyotyping analysis is still a useful tool in detecting chromosomal translocation in patients with ASD, given that array‐based comparative genomic hybridization technology can provide better resolution in detecting copy number variations of genomic DNA.

Identification of a microdeletion at Xp22.13 in a Taiwanese family presenting with Nance-Horan syndrome.

Nance-Horan syndrome (NHS) is a rare X-linked disorder characterized by congenital cataracts, dental anomalies and mental retardation. The disease has been linked to a novel gene termed NHS located at Xp22.13. The majority of pathogenic mutations of the disease include nonsense mutations and small deletions and insertions that lead to truncation of the NHS protein. In this study, we identified a microdeletion of ∼0.92 Mb at Xp22.13 detected by array-based comparative genomic hybridization in two brothers presenting congenital cataract, dental anomalies, facial dysmorphisms and mental retardation. The deleted region encompasses the REPS2, NHS, SCML1 and RAI2 genes, and was transmitted from their carrier mother who presented only mild cataract. Our findings are in line with several recent case reports to indicate that genomic rearrangement involving the NHS gene is an important genetic etiology underlying NHS.

No association of a dodecamer duplication in the human opposite paired (HOPA) gene with mental retardation and schizophrenia in Chinese patients from Taiwan

The human opposite paired-containing (HOPA) gene is believed to be a co-activator of the thyroid hormone receptor and involved in thyroid hormone signal transduction. The gene consists of 45 exons and includes a dodecamer duplication in exon 43, which has been reported to be associated with mental retardation, autism, psychiatric disorders and hypothyroidism. We were interested to know if the 12-bp duplication variant of the HOPA gene is a risk factor for mental retardation and schizophrenia in the Chinese population. We investigated the prevalence of the 12-bp variant in a sample of Chinese mental retardation and schizophrenic patients from Taiwan by PCR-based genotyping. None of the mentally retarded and schizophrenic patients were found to have this dodecamer duplication variant. Our results indicate that the HOPA polymorphism might be very rare in our population and is unlikely to be a major risk factor for mental retardation and schizophrenia in the Chinese population.

Molecular cytogenetic analysis and clinical manifestations of a case with de novo mosaic ring chromosome 7

AimClinical and molecular cytogenetic investigations of a newborn girl exhibiting facial dysmorphism with developmental delay.MethodsPhenotypic evaluation was first applied to examine the probands developmental status. Computed tomography and colour transcranial Doppler were used then to investigate her brain structure and function. Subsequently, chromosomal abnormalities were examined by karyotyping and fluorescent in situ hybridization was performed to investigate size of fragments lost at the two distal ends of the ring chromosome 7. In addition, multicolour banding was applied to rule out structural rearrangement occurs in between the ring chromosome 7.ResultsThe proband was born with mosaic supernumerary ring chromosome 7, without a normal karyotype detected in the peripheral blood lymphocytes. The distal arm of chromosome 7p (at least 255 kb from the telomere) was part of an extra ring chromosome 7. In addition, the distal arm of 7q, at least 8 kb from the telomere, was missing. There was no other chromosomal rearrangement detected by multicolour banding.InterpretationThis is the 19th reported case of complete ring chromosome 7 mosaicism and the first survived case with mosaic supernumerary ring 7 without a normal karyotype detected in the peripheral lymphocytes.

Clinical and molecular characterization of a transmitted reciprocal translocation t(1;12)(p32.1;q21.3) in a family co-segregating with mental retardation, language delay, and microcephaly

BackgroundChromosome translocation associated with neurodevelopmental disorders provides an opportunity to identify new disease-associated genes and gain new insight into their function. During chromosome analysis, we identified a reciprocal translocation between chromosomes 1p and 12q, t(1; 12)(p32.1; q21.3), co-segregating with microcephaly, language delay, and severe psychomotor retardation in a mother and her two affected boys.MethodsFluorescence in situ hybridization (FISH), long-range PCR, and direct sequencing were used to map the breakpoints on chromosomes 1p and 12q. A reporter gene assay was conducted in human neuroblastoma (SKNSH) and Chinese hamster ovary (CHO) cell lines to assess the functional implication of the fusion sequences between chromosomes 12 and 1.ResultsWe determined both breakpoints at the nucleotide level. Neither breakpoint disrupted any known gene directly. The breakpoint on chromosome 1p was located amid a gene-poor region of ~ 1.1 Mb, while the breakpoint on chromosome 12q was located ~ 3.4 kb downstream of the ALX1 gene, a homeobox gene. In the reporter gene assay, we discovered that the fusion sequences construct between chromosomes 12 and 1 had a ~ 1.5 to 2-fold increased reporter gene activity compared with the corresponding normal chromosome 12 sequences construct.ConclusionOur findings imply that the translocation may enhance the expression of the ALX1 gene via the position effect and result in the clinical symptoms of this family. Our findings may also expand the clinical phenotype spectrum of ALX1-related human diseases as loss of the ALX1 function was recently reported to result in abnormal craniofacial development.

Prenatal diagnosis of the maternal derivative chromosome der(15)t(Y;15)(q12;p13) in a dizygotic twin pregnancy

Sex chromosome translocations are unique and must be considered separately from translocations between autosomes. Here, we describe the first prenatal case of one twin fetus with an unbalanced translocation between chromosome Y and chromosome 15, presenting a 46,XY,der(15)t(Y;15) karyotype. The other twin had a normal 46,XY karyotype. Cytogenetic analysis of the parental chromosomes revealed that the father had a normal 46,XY karyotype, whereas the mother exhibited a 46,XX,der(15) t(Y;15) karyotype. Thus, the proband inherited this translocation from the mother. Fluorescence in situ hybridization analyses demonstrated that the breakpoint on chromosome Y involved a heterochromatin region (Yq12), while that on chromosome 15 involved a p-arm region (15p13). At 37 gestational weeks, healthy twins were delivered vaginally. We conclude that accurate identification of der(15) chromosomal content can facilitate not only prenatal diagnosis of a chromosomal aberration in one twin, but also prediction of the fetal phenotype.