Truncation of the Down Syndrome Candidate Gene DYRK1A in Two Unrelated Patients with Microcephaly Rikke S. Møller, Sabine Kübart, Maria Hoeltzenbein,

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Truncation of the Down Syndrome Candidate Gene DYRK1A in Two Unrelated Patients with Microcephaly Rikke S. Møller, Sabine Kübart, Maria Hoeltzenbein, Babett Heye, Ida Vogel, Christian P. Hansen, Corinna Menzel, Reinhard Ullmann, Niels Tommerup, Hans-Hilger Ropers, Zeynep Tümer, Vera M. Kalscheuer The American Journal of Human Genetics Volume 82, Issue 5, Pages 1165-1170 (May 2008) DOI: 10.1016/j.ajhg.2008.03.001 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Pictures and Laboratory Investigations of Patient 1 The pictures were taken when the patient was 3 months (A), 9 months (B), 14 months (C), and 24 months (D and E) of age. Magnetic-resonance imaging (F) at three months of age showed microcephaly and hypogenesis of corpus callosum. Cytogenetic analysis revealed a translocation with the karyotype 46,XY,t(9;21)(p12;q22) (G). For mapping of the breakpoints of the translocation, fluorescence in situ hybridization (FISH) was carried out with the use of BAC clones, according to standard procedures. The BAC clone RP11-315B15, which contains DYRK1A, spans the chromosome 21 breakpoint, as shown by signals on the normal and the derivative chromosomes (H). The American Journal of Human Genetics 2008 82, 1165-1170DOI: (10.1016/j.ajhg.2008.03.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 The Genomic Region Covered by the DYRK1A Gene The locations of the chromosomal breakpoints of the translocation patients are indicated by vertical arrows. The DYRK1A gene is organized in 17 exons (boxes) and has two transcription start sites, with exon 1 and exon 2 as alternative first exons. The use of these alternative start sites yields two major transcripts, DYRK1Aa (5182 nt) and DYRK1Ab (5287 nt), which are both truncated by the translocation breakpoints in patients 1 and 2. The bracket indicates that exon 3 is alternatively spliced. The chromosome band and base-pair positions are shown above the figure. The American Journal of Human Genetics 2008 82, 1165-1170DOI: (10.1016/j.ajhg.2008.03.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Clinical Pictures and Laboratory Investigations of Patient 2 The pictures were taken when the patient was 12 years of age. She has asymmetry of the head, flat philtrum, small upper lip, abnormal whorls of hair (A); microcephaly and large ears (B); pectus excavatum (C); and shortened and broad terminal phalanges of the hands and feet (D and E). Computerized tomography (F) at seven years of age and magnetic-resonance imaging (G and H) at 12 years of age showed microcephaly with head asymmetry and mild enlargement of the ventricles. Cytogenetic analysis revealed a translocation with the karyotype 46,XX,t(2;21)(q22;q22) (I). For mapping of the breakpoints of the translocation, FISH was carried out with the use of YAC, BAC, PAC, or cosmid clones according to standard procedures. The YAC clone 662A10, which contains DYRK1A, spans the chromosome 21 breakpoint, as shown by signals on the normal and the derivative chromosomes (J). Chromosome 21 breakpoint was fine mapped with Southern-blot hybridization (K). Genomic DNA from the patient (“P”) and the control (“C”) was digested with three restriction enzymes and hybridized with the breakpoint-spanning probe (chromosome position: 37,778,809–37,780,325). Aberrant bands representing the junction fragments are indicated by arrowheads. The American Journal of Human Genetics 2008 82, 1165-1170DOI: (10.1016/j.ajhg.2008.03.001) Copyright © 2008 The American Society of Human Genetics Terms and Conditions