Xin-Li Huang

Unmasking Kabuki syndrome: chromosome 8p22-8p23.1 duplication revealed by comparative genomic hybridization and BAC-FISH.

Kabuki syndrome (KS) is a multiple congenital anomalies/mental retardation syndrome that heretofore has had an unknown etiology. Although several cases with KS features have been reported with different chromosome anomalies, none have had an autosomal cytogenetic aberration in common. We found an 8p22–8p23.1 duplication, using comparative genomic hybridization (CGH) in six unrelated patients diagnosed with KS. This observation was confirmed using BAC‐FISH in all cases that delimited the duplicated region to approximately 3.5 Mb. No duplication of this region was found in two parents or 20 controls by either CGH or BAC‐FISH. Two out of two mothers of KS patients and one out of 20 controls were found to have a heterozygous submicroscopic inversion at 8p23.1. As the six patients with KS represent different races, this duplication may represent a common etiologic basis for this disorder.

Schizophrenia susceptibility gene locus at Xp22.3

Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau‐Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280–283) to have a de novo partial duplication of Xp. At that time, she was a 24‐year‐old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16–18 cM. Patient 2 is a 14‐year‐old girl with short stature, learning disabilities, and paranoid schizophrenia. High‐resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10–12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia.

Familial paragangliomas : Linkage to chromosome 11q23 and clinical implications

Familial paragangliomas (PGL), or glomus tumors, are slow-growing, highly vascular, generally benign neoplasms usually of the head and neck that arise from neural crest cells. This rare autosomal-dominant disorder is highly penetrant and influenced by genomic imprinting through paternal transmission. Timely detection of these tumors affords the affected individual the opportunity to avoid the potential morbidity associated with surgical removal, and mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q22.3-q23, has been reported, suggesting heterogeneity. We evaluated three multigenerational families with hereditary PGL, including 19 affected, and 59 unaffected and potentially at-risk individuals. Numerous microsatellite markers corresponding to each candidate region were tested in all members of the three families. Confirmation of linkage to 11q23 was established in all three families. The inheritance pattern was consistent with genetic imprinting. Using these data, we were able to provide presymptomatic diagnosis with subsequent removal of tumor from one individual, and to start several others on an MRI surveillance protocol.

A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a patient with autism

A De Novo Balanced Translocation Breakpoint Truncating the Autism Susceptibility Candidate 2 (AUTS2) Gene in a Patient With Autism Xin-Li Huang, Ying S. Zou, Tom A. Maher, Stephanie Newton, and Jeff M. Milunsky* Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts Department of Pathology, Boston University School of Medicine, Boston, Massachusetts

The shorter zinc finger protein ZNF230 gene message is transcribed in fertile male testes and may be related to human spermatogenesis

The zinc finger gene family represents one of the largest in the mammalian genome, with several of these genes reported to be involved in spermatogenesis. A newly discovered gene has been identified that is expressed abundantly in the testicular tissue of fertile men as determined by mRNA differential display. The gene encodes a C(3)HC(4)-type zinc finger protein motif (ring finger motif) consistent with a role in pre-meiotic or post-meiotic sperm development. The gene was named ZNF230 and mapped to the short arm of chromosome 11 (11p15). ZNF230 has two transcripts, of 1 kb and 4.4 kb in length. The shorter 1 kb transcript was only detected in testicular tissue whereas the longer 4.4 kb transcript was not detected in testis but was found in several other tissues. The lack of detectable ZNF230 expression in azoospermic patients by reverse transcriptase-mediated PCR analysis is interpreted to mean that this gene is involved in maintaining normal human male fertility.

A locus for autosomal recessive achromatopsia on human chromosome 8q

Autosomal recessive achromatopsia is a rare disorder characterized by total absent color vision, nystagmus, photophobia, and visual impairment, frequently leading to ‘legal blindness’. The primary defect is at the photoreceptor level, with retinal cones being absent or defective. The first locus for this disorder was mapped to chromosome 2q11. Here, we confirm the genetic mapping of a locus discovered in our studies of a kindred with Irish ancestry, but no known consanguinity, in which 5 of 12 children are affected. We have mapped the locus in this disorder in this family to chromosome 8q. Available data now narrow the region containing the putative gene to 1.2 cM.

Isolation, characterization, and mapping of a novel human KRAB zinc finger protein encoding gene ZNF463.

A novel human KRAB (Krüppel associated box) type zinc finger protein encoding gene, ZNF463, was obtained by mRNA differential display and RACE. It consists of 1904 nucleotides and encodes a protein of 463 amino acids with an amino-terminal KRAB domain and 12 carboxy-terminal C2H2 zinc finger units. The gene is mapped to chromosome 19q13.3 approximately 4 by FISH. As from Northern blot analysis ZNF463 is only expressed in testis, RT-PCR indicates that ZNF463 is expressed more highly in normal fertile adults than in fetus and azoospermic patients suggesting that it may play a role in human spermatogenesis.

Further delineation of the critical region for the 9p-duplication syndrome†

Further Delineation of the Critical Region for the 9p-Duplication Syndrome Ying S. Zou,* Xin-Li Huang, Masamichi Ito, Stephanie Newton, and Jeff M. Milunsky Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts Department of Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts

Characterization of an analphoid supernumerary marker chromosome derived from 15q25→qter using high‐resolution CGH and multiplex FISH analyses

Supernumerary marker chromosomes (SMCs) without detectable alphoid DNA are predicted to have a neocentromere and have been referred to as mitotically stable neocentromere marker chromosomes (NMCs). We report the molecular cytogenetic characterization of a new case with analphoid NMC derived from 15q25→qter using high‐resolution comparative genomic hybridization (HR‐CGH) and multiplex fluorescence in situ hybridization analyses with various α‐satellite DNA probes, all‐human‐centromere probe (AHC), whole chromosome painting probes, and a subtelomere probe. The propositus is a dysmorphic infant who, at age 3 months, showed accelerated growth, partial deafness, and a phenotype similar to that of the eight previously reported cases of distal 15q tetrasomy. Chromosome studies showed that he had a de novo extra SMC in 80% of cells examined. HR‐CGH revealed rev ish enh(15)(q25qter). Molecular cytogenetic analysis and molecular DNA polymorphism study demonstrated that this extra SMC is an NMC containing an inverted duplication of the distal long arm of chromosome 15 (tetrasomy 15q25→qter) which originated paternally, i.e. ish der(15)(qte→q25::q25[neocen]→qter)(AHC–, CEP15–, WCP15+, PCP15q++). This case further elucidates the phenotype related to tetrasomy of this specific chromosome segment and represents a new report of a neocentromere on distal chromosome 15q suggesting that this region appears to be susceptible to the formation of neocentromeres.

Delineation of a supernumerary marker chromosome utilizing a multimodal approach of G-banding, fluorescent in situ hybridization, confirmatory P1 artificial chromosome fluorescent in situ hybridization, and high-resolution comparative genomic hybridization

We describe the structure of a supernumerary marker in a child who presented with a right atretic ear and multiple congenital anomalies. Using G‐banding, fluorescent in situ hybridization (FISH), P1 artificial chromosome FISH and high‐resolution comparative genomic hybridization (CGH), the marker was demonstrated to be a derivative chromosome resulting from malsegregation of a paternal 8;22 translocation: 47,XY, +der(22)t(8;22)(q24.1; q11.2). This case is noteworthy because the marker, while sharing similarities to der(22) in the Cat Eye syndrome (CES), also contains chromosome 8q material. This partial 8q trisomy confounds the diagnosis of CES associated with pure trisomy or pure tetrasomy 22q. The paternal translocation is noted with prolonged infertility and oligospermia, which again highlights the utility and necessity of chromosome analysis in this setting.