The human Y chromosome

Background Pallister-Killian syndrome is a rare, sporadic condition caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). The main features are intellectual disability, seizures, dysmorphic features and a variety of congenital malformations. Most available information comes from individual case reports. We report the results of a British study into Pallister-Killian syndrome, which is the first to provide comprehensive data on a population-based sample. Method A detailed phenotypical study was carried out in Great Britain. All individuals with Pallister-Killian syndrome were eligible to participate. Each participant underwent a structured history, developmental assessment and clinical examination. Buccal mucosal samples were analysed by interphase fluorescence in situ hybridization (FISH) and blood samples by array comparative genomic hybridization (CGH). Genotype-phenotype correlations were sought in these tissues and existing skin biopsy reports. Results Twenty-two patients with Pallister-Killian syndrome, ranging from 4 months to 31 years were recruited and comprehensive data on each obtained. The birth incidence was 5.1 per million live births. Array CGH only suggested the diagnosis in 15.8% but buccal FISH could have made the diagnosis in 75.0%. There was no genotype-phenotype correlation in any of the tissues studied. This study shows that the high birth weights and profound intellectual disability classically described in Pallister-Killian syndrome are not universal. Mild or moderate intellectual disability was present in 27.6% of this cohort and all birth weights were within 2.67SD of the mean. New features which have not previously been recognised as part of Pallister-Killian syndrome include anhydrosis/ hypohydrosis and episodic hyperventilation, suggesting involvement of the autonomic system.

https://jmg.bmj.com/content/jmedgenet/52/7/454.full.pdf

Pallister-Killian syndrome: a study of 22 British patients

Objective
Advance knowledge about the mechanism of isochromosome formation.

Methods
Echographic examination of the foetus. G- and/or T-banded chromosome and FISH analysis using chromosome 12p subtelomeric probes on short- and long-term CVS cultures, amniocytes and foetal fibroblasts. Polymorphic CA repeat analysis on DNA from the foetus and both parents.

Results
Short-term CVS cultures showed a 46,XX karyotype, whilst long-term CVS cultures showed a 47,XX,+12 karyotype. FISH on amniocytes indicated 2, 3 and 4 signals. Foetal fibroblasts showed both 47,XX,+12 and 47,XX,+i(12)(p10) karyotypes. DNA analysis revealed the isochromosome to be paternal in origin, whilst the other two foetal chromosomes 12 were maternal, part iso- and part heterodisomy.

Conclusion
The cytogenetic and DNA constitution of the foetus indicated the isochromosome 12p to be of paternal origin, and implied post-zygotic formation of the isochromosome 12p in the Pallister–Killian syndrome. Copyright © 2004 John Wiley & Sons, Ltd.

Post-zygotic origin of isochromosome 12p.

This is a multi-authored volume of nine chapters building on two earlier and evidently successful editions (1986, 1992). Embedded in the chapters is a comprehensive range of 17 main protocols (with subsections) starting with cell culture techniques (Chapter 1) and moving on through banding, basic FISH, multi-coloured FISH, and so on, and ending with diseases for which chromosome analysis is used diagnostically. This is a practitioners book, and has to be essential reading for trainees in the art. Its natural home is in the laboratory by the workplace. Those of us who teach human cytogenetics will also ¢nd many interesting and useful parts to give us an anchor for our knowledge base, and to catch a £avour of the ‘life’ of someone working in the practice of human cytogenetics. I had expected a heavier lean towards FISH in all its manifestations, but was interested to learn that those at the workface still rely heavily on G-banding. This explains the ideograms of chromosomes, in the appendix section, at three levels of resolution of 400, 500 and 550^850 bands per haploid set. The appendix also has a useful list of suppliers and a small new section on safety considerations. There is also a useful glossary of many unfamiliar and subject-speci¢c terms. The chapters cover a wide range of topics, including: cytogenetics of myeloid leukaemia; acute lymphoblastic leukaemia; molecular cytogenetics techniques; solid tumour cytogenetics; in-vivo mutagen-induced chromosome damage in lymphocytes; and chromosome instability syndromes. The chapters are each distinctive and, collectively, they cover a broad spectrum of genetic disorders. The common theme is some description of methodology and protocols, clinical descriptions and cytogenetics features. In total, this amounts to an atlas of the cytogenetics of various abnormalities, a compendium of methodology and a valuable and comprehensive reference work. This book will be snapped up eagerly by those who knew and treasured the earlier editions.

Human Cytogenetics: Malignancy and Acquired Abnormalities, Third Edition, A Practical Approach

Pallister-Killian syndrome is a sporadic disorder caused by the presence of mosaic tetrasomy of the short arms of chromosome 12. Case reports of children with Pallister-Killian syndrome have described a range of developmental and behavioral outcomes, but no systematic studies of these outcomes exist. The objective of this study was to describe developmental and behavioral characteristics of individuals with Pallister-Killian syndrome participating in a national meeting of families and their affected children. Sixteen individuals with Pallister-Killian syndrome, ages 16 months to 19 years, were studied using questionnaires and direct interview. Among the 16 patients enrolled in the study, 3 probands were between 16 and 19 months, and had severe developmental delay. Among the rest of the 13 probands older than 24 months, 11 children had a developmental level of less than 8 months age equivalent. They were non-ambulatory, non-verbal, and passive, requiring extensive assistance in daily living. There were two higher functioning children who were ambulatory, and verbal. One of these children met criteria for Autism on the Autism Diagnostic Interview-Revised. Thus, although most individuals with Pallister-Killian syndrome studied showed profound intellectual disability and sensory impairments, individuals with Pallister-Killian syndrome can have mild to moderate intellectual disability. Therefore, in individuals with physical examination findings of Pallister-Killian syndrome, formal diagnostic testing should be considered, even in individuals with mild to moderate intellectual disability. Further studies will be needed to determine if these higher functioning children with Pallister-Killian syndrome are at increased risk for autism.

Developmental and behavioral characteristics of individuals with Pallister-Killian syndrome.

Pallister-Killian syndrome is a clinically recognizable syndrome, usually due to a tissue-limited mosaicism for a supernumary 12p isochromosome (i12p). Here we report an unusual case with tetrasomy/trisomy/disomy 12p mosaic in fibroblasts and trisomy/disomy 12p mosaic in lymphocytes. The tetrasomy 12p was due to an i12p, the trisomy 12p to a single 12p marker. Both marker chromosomes were investigated with conventional cytogenetic techniques and fluorescent in situ hybridization (FISH). Stability under culturing conditions was studied. DNA-analysis revealed prezygotic maternal origin of the extra 12p material. Clinically, the patient seems to have less retardation than most patients with Pallister-Killian syndrome.

Clinical, cytogenetic, and molecular observations in a patient with Pallister-Killian-syndrome with an unusual karyotype.

Background: Cytogenetic analysis, Y-chromosome microdeletion screening, FISH techniques and other genetic methods have helped in finding the causes of infertility in azoospermic or severe oligoazoospermic cases in the last decade. Objective: In the present study, we characterized an abnormal Y-chromosome, detected as a mosaic in an azoospermic male ascertained for infertility. Materials and Methods: Chromosome analysis, using G, Q and C banding techniques and FISH analyses with several different DNA probes specific for Y and X chromosome sequences [XY centromeric α-satellite, Y non-α-satellite III, LSI-probes of the Y chromosome, WCP of Chromosome Y, SRY gene, subtelomeric Xp and Yp, which cover the SHOX (short stature-homeobox containing) gene, and subtelomeric Xq and Yq probes] were performed. A total of 20 sequence tagged sites were analyzed using primer sets specific for the Y-chromosome microdeletion loci. The primers were chosen to cover AZFa, AZFb, and AZFc regions as well as the SRY gene. Results: Chromosome analysis revealed a gonosomal mosaicism of monosomy X (51%) and a pseudodicentric Y (49%) chromosome: mos 45, X/46,X psu dic (Y) (qter→p11.32 :: p11.2→qter). Molecular genetic studies did not show deletions in the AZFabc regions, but a deletion was found in the short arms of the dicentric Y chromosome. One of the SRY genes was also missing. Conclusion: The azoospermia in this patient could be explained by either the presence of an abnormal Y-chromosome that cannot form a sex vesicle (which appears to be necessary for the completion of meiosis process and the formation of sperm), or the presence of the 45, X cell line.

/pdf/cytogenetic-and-molecular-genetic-analysis-of-dicentric-y-2crkl8myid.pdf

Jurgen Gebauer

Papers

Clinical, cytogenetic, and molecular observations in a patient with Pallister-Killian-syndrome with an unusual karyotype.

Cytogenetic and molecular genetic analysis of dicentric Y chromosome and its relation to male azoospermia