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207 Perry Parkway Gaithersburg, MD 20877 • T 1 888 729 1206 (Toll-Free), 1 301 519 2100 • F 1 201 421 2010 • E [email protected] • www.genedx.com Figure 1. Oligo array CGH profiles of chromosome 8 [A] and chromosome 12 [B], showing the 8p23.2p23.3 terminal deletion of ~ 7 Mb, and the concomitant terminal duplication of 8.3 Mb in 12p. Methods Recurrent constitutional reciprocal non-Robertsonian chromosome translocations are rare. To our knowledge, there are only three such balanced translocations reported in the literature: the most common one is t(11;22) (q23;q11), while t(8;22) (q24.13;q11.21) and t(4;8)(p16;p23) are less frequently seen. 1,2 Recurrent unbalanced translocations, most notably der(4)t(4;11)(p16.2;p15.4), have been also reported. 3 Here we report an apparently recurrent unbalanced translocation between the short arms of chromosomes 8 and 12 [der(8)t(8;12)(p23.1;p13.31)] found in three cases referred to our clinical diagnostic laboratory for chromosomal microarray (CMA). • These three blood specimens were sent to our clinical genetics laboratory between August 2014 and May 2017 for CMA and were tested by a custom-designed 180K genome array with SNP (Agilent). During this time, total 14,607 whole genome microarray studies were performed. • Parental testing was performed by fluorescence in situ hybridization (FISH) using probes from within the deleted and duplicated regions (Empire Genomics) on two of the three families; the third family was not available for FISH testing. • Phenotypic information was available on two of the probands and compared to the three cases reported in the literature Background Results Conclusions • CMA revealed a ~7 Mb terminal deletion at 8p23.2p23.3 and a concomitant ~8.3 Mb terminal duplication of 12p13.33p13.31 in three probands (see Figure 1 ). • Metaphase FISH using probes from within the deleted and duplicated regions performed on two probands showed that these aberrations were secondary to a derivative chromosome 8, der(8)t(8;12)(p23.1;p13.31) (see Figure 2A). • Metaphase FISH on parental blood in two of the families revealed a normal hybridization, consistent with a de novo occurrence of the unbalanced translocation in the probands (see Figure 2B). • Common clinical features of individuals with der(8)t(8;12)(p23.1;p13.31) include motor and language delay, hypotonia, childhood onset epilepsy, and autistic features. Additional features observed in more than one patient were facial dysmorphism, umbilical hernia, CNS abnormalities, and eye problems (see Table 1 ). Only three patients 1,4 with a similar derivative chromosome 8 [der(8)t(8;12)(p23.1;p13.31)] resulting in terminal deletions and duplication of 8p and 12p, respectively, have been reported in the literature previously to our knowledge. We identified an additional three such patients with the same derivative chromosome (0.02%) from 14,607 consecutive CMA cases. Parental FISH studies on two of our patients and one reported in the literature 4 showed no predisposing balanced rearrangement, consistent with the de novo origin in all cases in which inheritance has been studied. The 8p23.1 and 12p13.31 chromosome regions are known to contain highly homologous low-copy repeat (LCR) clusters which may predispose them to rearrangement. In summary, the der(8)t(8;12) appears to be a recurrent de novo unbalanced translocation mediated by large LCRs and associated with the phenotype of developmental delay, hypotonia, childhood onset epilepsy, and autistic features. 1. Giglio S, et al., Am J Hum Genet 2002, 71:276-285. PMID: 12058347 2. Hermetz KE1, et al., Mol Cytogenet. 2012 Jan 19;5(1):6. PMID: 22260357 3. Ou Z, et al., Genome Res 2011, 21:33-46. PMID: 21205869 4. Margari L, et al., Am J Med Genet A. 2012 Jul;158A(7):1713-8 PMID: 22639464 References RECURRENT UNBALANCED CONSTITUTIONAL CHROMOSOMAL TRANSLOCATION BETWEEN CHROMOSOMES 8 AND 12, DER(8)T(8;12)(P23.1;P13.31), DETECTED IN THREE PATIENTS WITH SIMILAR PHENOTYPE Dongli Huang, PhD 1 ; Ludmila Matyakhina, PhD 1 ; Andrea Wray MS 1 ; Valery Nelson MS 1 ; Roger Ladda MD 2 ; Susan Sell, MS 2 ; Ronald Davis, MD 3 ; Jennifer Richards, MS 3 ; John Condie, MD 4 ; Jeanne Meck, PhD 1 1 GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877; 2 Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, PA 17033; 3 Pediatric Neurology PA 7485, Sandlake Commons Blvd, Orlando, FL 32819; 4 St. Luke’s Children’s Neurology, 100E Idaho St., Boise, ID 83712 Clinical Features Patient 1 (this study) Patient 2 (this study) Patient 3 (this study) Ou Z, et al. (2011) patient 5 and 6 Margari L, et al. (2012) patient Developmental delay/ Intellectual disability + + N/A N/A + Seizures + - N/A N/A + Facial dysmorphism including a round face with prominent cheeks, a flat and broad nasal bridge - + N/A N/A + Hypotonia + + N/A N/A + Autistic features/Autism + - N/A N/A - Behavior issues + - N/A N/A + Umbilical hernia + + N/A N/A + CNS abnormalities + + N/A N/A + Congenital heart disease + - N/A N/A - Eye/vision issues + + N/A N/A - Pleasant/easy personality + - N/A N/A + Constipation + + N/A N/A - Other features obesity, undescended testes, Hashimoto's hypothroidism, facial diplegia, pseudobulbar palsy, wide-based gait joint hyperextension, large birth weight, intestinal malrotation with Meckel’s diverticulum poor sleep, asthma, eczema, hypopigmented spots, macrocephaly, excellent memory N/A N/A dyspraxia Table 1. Clinical Features Observed in Individuals with der(8)t(8;12)(p23.1;p13.31) Figure 2. FISH analysis in probands and their parents. [A] a representative FISH image of a proband. [B] a representative FISH image of a parent showing normal hybridization pattern for 8p and 12p. FISH probes used: RP11-43A14 (8p23.3; Orange signal; Empire Genomics), RP11-958H19 (12p13.33; Green signal; Empire Genomics), and control probe D8Z2 (specific to the centromere of chromosome 8; Aqua signal; Abbott Molecular). In Fig 2A the proband’s hybridization shows 3 green signals (12p), 2 aqua signals (chr8 centromere), and only 1 red signal (8p), which is consistent with der(8)t(8;12). 8 12 der(8)t(8;12) 12 Orange: 8p23.3, Green: 12p13.33, Aqua: 8p11.1q11.1 A 12 12 8 8 Orange: 8p23.3, Green: 12p13.33, Aqua: 8p11.1q11.1 B FBXO25 DLGAP2 CLN8 ARHGEF10 MYOM2 CSMD1 MCPH1 XKR5 defensins WNK1 CACNA1C CCND2 FGF23 KCNA1 KCNA5 VWF TNFRSF1A VAMP1 CHD4 ATN1 C1R GDF3 Segmental duplications 1,000,000 2,000,000 3,000,000 4,000,000 5,000,000 6,000,000 7,000,000 1,000,000 2,000,000 3,000,000 4,000,000 5,000,000 6,000,000 7,000,000 8,000,000 A. Chromosome 8 B. Chromosome 12
