Kabuki Syndrome in 48 well-defined new individuals our data show it is underrepresented in young fathers and overrepresented in older fathers

Am J Med Genet A. 2005 Jan 30;132(3):265-72. Links
Further delineation of Kabuki syndrome in 48 well-defined new individuals.Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, Gillessen-Kaesbach G, Graham JM Jr, Grebe TA, Gripp KW, Hall BD, Hennekam R, Hunter A, Keppler-Noreuil K, Lacombe D, Lin AE, Ming JE, Kokitsu-Nakata NM, Nikkel SM, Philip N, Raas-Rothschild A, Sommer A, Verloes A, Walter C, Wieczorek D, Williams MS, Zackai E, Allanson JE.
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. llarmstrong@cw.bc.ca

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined. (c) 2004 Wiley-Liss, Inc.

PMID: 15690370 [PubMed - indexed for MEDLINE]



1: Am J Med Genet A. 2005 Jan 30;132(3):260-2. Links
Autoimmune disorders in Kabuki syndrome.Ming JE, Russell KL, McDonald-McGinn DM, Zackai EH.
Division of Human Genetics and Molecular Biology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. jeming@mail.med.upenn.edu






Kabuki syndrome is associated with abnormalities in multiple organ systems. While many of the anomalies are congenital malformations, other clinical manifestations may not appear until later in childhood. Among these associated conditions, autoimmune abnormalities have been described in several patients. These include idiopathic thrombocytopenic purpura (ITP), hemolytic anemia, thyroiditis, and vitiligo. In this report, we describe five affected patients with autoimmune manifestations. Four patients had ITP, and two of these patients had concurrent hemolytic anemia. The fifth patient had vitiligo. Two of the patients with ITP had a chronic and relapsing course. Of note, some of these patients also had hypogammaglobulinemia. The autoimmune disorders may be manifestations of abnormal immune regulation. We conclude that Kabuki syndrome is associated with an increased incidence of autoimmune disorders. In addition, the presence of an underlying immune defect may predispose these children to a chronic course of these autoimmune conditions. (c) 2004 Wiley-Liss, Inc.

PMID: 15523604 [PubMed - indexed for MEDLINE]




Paternal Age
Data from the study and the literature suggest an association with advanced paternal age. The average paternal and maternal ages in this study are 34 years (n = 39) and 28.9 years (n = 42), respectively. The average paternal age did not vary with birth year (data not shown). the same data and effect in a complimentary way. These plots show that observed Kabuki syndrome births are underrepresented in young fathers (where the ratios are below one) and overrepresented in older fathers (where the ratios are above one). In the absence of a parental age effect, the ratio would be approximately one across all ages, which is the pattern seen for the maternal age data.




. The average paternal ages of all series are greater than the US means derived from vital statistics, and the mean paternal age of 27 years quoted by The American College of Medical Genetics in their Statement of Guidance for Genetic Counseling in Advanced Paternal Age [American College of Medical Genetics Statement on Guidance for Genetic Counseling in Advanced Paternal Age, [1996]]. has an average paternal age below its control paternal age; however, interpretation may require caution. Firstly, there is evidence that this series is causally heterogeneous, including, for example, children with chromosome abnormalities (2 of 62 have unbalanced karyotype). Secondly, the authors indicate that some of the individuals resembled a parent. If these represent non-sporadic diagnoses, their inclusion would dilute any paternal age effect.





Conditions including achondroplasia, Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, and the type 2 multiple endocrine neoplasias show strong paternal mutation bias and paternal age effects. Each is due to a point mutation. Other disorders such as neurofibromatosis type 1 show a milder paternal mutation bias and paternal age effect, and the disease causing mutations are heterogeneous with point mutations comprising a subset [Crow, [2000]]. Our data suggest that Kabuki syndrome may be related to mutations associated with paternal aging.
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Reviews Genetics 1, 40-47 (2000); doi:10.1038/35049558


THE ORIGINS, PATTERNS AND IMPLICATIONS OF HUMAN SPONTANEOUS MUTATION
James F. Crow

Summary

Germline base substitution mutations occur more frequently in males than in females, especially in older males.
The main explanation for the sex and age effect is that a much larger number of germline divisions occurs in the male than in the female, and continues throughout male adulthood.
Point mutations at some loci occur almost exclusively in males, whereas others have a smaller excess, roughly ten times more than in females. Which is more typical remains to be determined.
For mutations other than point mutations, sex biases in the mutation rate are very variable. However, small deletions are more frequent in females.
The total rate of new deleterious mutations for all genes is estimated to be about three per zygote. This value is uncertain, but it is likely that the number is greater than one.
It is suggested that quasi-truncation selection is the principal explanation for how the population can rid itself of a large number of mutations with a relatively low fitness cost.
Since this form of selection is effective only with sexual reproduction, perhaps the fact that humans reproduce sexually has made it possible to have such a long life cycle.




Author biography
James F. Crow received his Ph.D. from the University of Texas in 1941. After seven years at Dartmouth College, he moved to the University of Wisconsin where he has been since and is now emeritus professor of genetics. He is a member of the National Academy of Sciences as well as a foreign member of the Japan Academy. His research interests are in population genetics, both theoretical and experimental. In addition to journal articles, he is the co-author of An Introduction to Population Genetics Theory with M. Kimura.