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A Novel Microdeletion/Microduplication Syndrome of 19P13.13 Michelle Dolan, MD1, Nancy J

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A Novel Microdeletion/Microduplication Syndrome of 19P13.13 Michelle Dolan, MD1, Nancy J ARTICLE A novel microdeletion/microduplication syndrome of 19p13.13 Michelle Dolan, MD1, Nancy J. Mendelsohn, MD2,3, Mary Ella Pierpont, MD, PhD2,3,4, Lisa A. Schimmenti, MD4, Susan A. Berry, MD4, and Betsy Hirsch, PhD1 Purpose: Whole genome interrogation by array-based comparative ants (CNVs) of clinical significance that involve too small a chro- genomic hybridization has led to a rapidly increasing number of dis- mosomal region to be detected by conventional cytogenetics have coveries of novel microdeletion and/or microduplication syndromes. been identified for every chromosome pair in the human karyotype. We here describe the clinical and cytogenomic correlates of a novel For some CNVs, variability in expression and penetrance of clin- microdeletion/microduplication of 19p13.13. Methods: Among pa- ical manifestations has complicated the establishment of clinical tients referred to the Cytogenetics laboratory for array-based compara- significance. For others, documenting clinical relevance has been tive genomic hybridization analysis, we identified four with a deletion facilitated by association of the CNV with more consistent and and one with a duplication within 19p13.13. Confirmatory fluorescence specific phenotypic findings, and with de novo inheritance. We in situ hybridization and parental studies were performed. Detailed here describe a CNV for chromosome 19p13.13 that meets the latter criteria. Despite the fact that chromosome 19 is one of the clinical findings and array profiles were reviewed and compared. ϳ Results: Patients with deletions of 19p13.13 share a unique constellation of most gene-rich chromosomes ( 2000 genes within 59 Mb), to phenotypic abnormalities. In addition to developmental disabilities, the date, there have been only a few published reports of individuals 5–10 microdeletion manifested in overgrowth, macrocephaly, and ophthalmo- with deletions involving 19p. Critical to identifying this mi- logic and gastrointestinal findings; in contrast, the single microduplication crodeletion/microduplication syndrome was the consensus charac- manifested in growth delay and microcephaly. Conclusion: The consistent terization of the clinical findings by four clinical geneticists and constellation of clinical findings associated with copy number variation of correlation of those findings with the microarray data. this region warrants the designation of microdeletion/microduplication syn- drome of 19p13.13. An approximately 311–340 Kb smallest region of overlap encompassing 16 genes was identified. Candidate genes include MATERIALS AND METHODS MAST1, NFIX, and CALR. Identification of this syndrome has led to Subjects recommendations for diagnostic work-up and follow-up of patients with this copy number variant. Integration of detailed clinical and array data Five patients were referred for diagnosis to genetics clin- is critical for advancing both patient care and human genomic research. ics at the University of Minnesota Amplatz Children’s Hos- Genet Med 2010:12(8):503–511. pital and at the Children’s Hospitals and Clinics of Minne- sota. Array-CGH was ordered as a component of the standard Key Words: array CGH, chromosome 19p13, microdeletion, microdu- work-up for patients with unexplained multiple anomalies plication, syndrome and/or developmental disabilities. The patients’ ages ranged from 5 to 26 months at the time of first examination; each was evaluated by one of four clinical geneticists. Participa- he incorporation of microarray technology into the routine tion in this study to permit sharing of data and publication of Tassessment of patients with unexplained developmental dis- results was approved by the Institutional Review Boards of abilities and/or phenotypic abnormalities has resulted in the rapid both the institutions. Informed consent was obtained from the discovery of numerous recurrent microdeletions/microduplica- parents of these patients. tions. For example, over a period of only 2 years, previously undetected losses and/or gains for the genomic regions of 1q21.11,2 and 16p11.23,4 have become widely recognized as potential etio- Array-based comparative genomic hybridization logic factors for autism and related disorders. Copy number vari- analysis DNA from the patients’ peripheral blood was isolated, restric- tion digested, and labeled with fluorochrome cyanine 5 using From the 1Department of Laboratory Medicine and Pathology, University of random primers and exo-Klenow fragment DNA polymerase. 2 Minnesota Medical School, Minneapolis, Minnesota; Division of Pediatrics, DNA from pooled sex-matched controls was labeled concurrently Department of Genetics, Children’s Hospitals & Clinics of Minnesota, Minneapolis, Minnesota; 3Division of Pediatrics, Department of Genetics, with fluorochrome cyanine 3. The DNA of the patient and the Children’s Hospitals & Clinics of Minnesota, St. Paul, Minnesota; and control was combined, and an array-based comparative genomic 4Departments of Pediatrics and Ophthalmology, Institute of Human Genet- hybridization (aCGH) was performed with a customized 44K oli- ics, Division of Genetics and Metabolism, University of Minnesota Medical gonucleotide array that included targeted regions of enriched cov- School, Minneapolis, Minnesota. erage on a backbone of average overall median probe spacing of 35 Michelle Dolan, Department of Laboratory Medicine and Pathology, Uni- Kb. To estimate with greater precision the stop and start points for versity of Minnesota Medical School, Mayo Mail Code 609, 420 Delaware the patient with the smallest deletion (Patient 3), a 180K array with St. SE, Minneapolis, MN 55455. E-mail: [email protected]. an average tiled spacing of 13 Kb was performed (Agilent Tech- Disclosure: The authors declare no conflict of interest. nologies, Santa Clara, CA). The ratio of patient to control DNA for Submitted for publication February 23, 2010. each oligonucleotide was calculated using Feature Extraction soft- ware 9.1 or 10.5 (Agilent Technologies), and analysis was per- Accepted for publication April 29, 2010. formed using DNA Analytics 4.0.85 (Agilent Technologies). Sta- Published online ahead of print July 6, 2010. tistical algorithms used for analysis included ADM1 and ADM2 DOI: 10.1097/GIM.0b013e3181e59291 (Agilent Technologies) with threshold values set at an absolute Genetics IN Medicine • Volume 12, Number 8, August 2010 503 Dolan et al. Genetics IN Medicine • Volume 12, Number 8, August 2010 Table 1. Clinical and cytogenetic features of patients with loss or gain within 19p13.12-p13.13 Clinical and cytogenetic features of patients with loss or gain within 19p13.12-p13.13 Patients 12 345 Cytogenetic Del 19p13.13-p13.2 Del 19p13.13-p13.2 Del 19p13.13 Del 19p13.13-p13.2 Dup 19p13.12-p13.2 imbalance Breakpoints 12,498,237–13,126,508 12,536,641–13,794,080 12,793,474–13,104,643 12,411,017–13,120,904 12,601,112–14,488,238 (minimum) Size (min) 0.6 Mb 1.3 Mb 0.3 Mb (311 Kb) 0.7 Mb 1.9 Mb Breakpoints 12,476,664–13,178,511 12,521,732–13,854,243 12,779,366–13,120,858 12,335,402–13,126,464 12,582,355–14,503,887 (maximum) Size (max) 0.7 Mb 1.3 Mb 0.3 Mb (341 Kb) 0.8 Mb 1.9 Mb First examination Age 2 yrs 2 yrs 0.75 yrs 0.5 yrs 3 yrs Length (%ile) 50th Ͼ95th 90th 90th Ͻ5th Weight (%ile) 75th Ͼ95th 50–75th 90th 25th OFC (%ile) Ͼ97th Ͼ95th Ͼ98th Ͼ98th ϽϪ2SD Craniofacial Macroceph, frontal Macroceph, frontal Macroceph, frontal Macroceph, frontal Microceph, frontal bossing bossing, downslanting bossing, downslanting bossing bossing, downslanting PF PF PF Ophthalmologic Esotropia, nystagmus, Optic nerve hypoplasia, OA, exotropia Optic nerve hypoplasia, Nystagmus poor fixation exotropia exotropia, nystagmus GI Chronic diarrhea Abd. pain, vomiting, None Abd. pain, vomiting, Abd. pain, vomiting, poor feeding celiac disease FTT (G-tube) Brain Normal Mild atrophy, frontal Absent rostral corpus Chiari I malformation Normal MRI lobes callosum, cystic with syrinx lesion Seizures ϪϪϩϩϩ Hypotonia ϩϪϩϩTorticollis Developmental Full scale IQ 49 18-mo skills at 3 yrs; Almost nonverbal Mod. speech delay; 21–29 mo skills at delay mkd speech delay needs special ed. 4.5 yrs; mkd speech delay Last examination Age 6 yrs 3 yrs 14.5 yrs 9.5 yrs 7 yrs Height (%ile) 86th Ͼ95th 50th 75th Ͻ3rd Weight (%ile) 55th Ͼ95th 10–25th 50–75th 50th OFC (%ile) Ͼ97th Ͼ95th Ͼ98th Ͼ98th Ϫ2SD Del, deletion; dup, duplication; NM, not mentioned; NE, not evaluated; macroceph, macrocephaly; micro, microcephaly; brachy, brachycephaly; OA, optic atrophy; OFC, occipitofrontal circumference; PF, palpebral fissures; abd., abdominal; mod, moderate; mkd, marked; ed, education. value of 0.3 on a log2 scale and with a requirement of three probands and to rule out an interchromosomal rearrangement in consecutive oligos meeting the threshold criteria. the parents that, if found, would significantly impact recurrence risks. The BACs selected for FISH probes were RP11-654K9 Fluorescence in situ hybridization analysis (encompassing MAST1), RP11-963I8 (encompassing NFIX), Fluorescence in situ hybridization (FISH) was performed to RP11-14L14 (encompassing CACNA1A), and for Patient confirm the presence of a deletion and/or duplication in the 5, RP11-56K21 (encompassing PKN1). Stabs for RP11-654K9, 504 © 2010 Lippincott Williams & Wilkins Genetics IN Medicine • Volume 12, Number 8, August 2010 Microdeletion/microduplication syndrome of 19p13.13 Table 1. Continued Clinical and cytogenetic features of patients with loss or gain within 19p13.12-p13.13 Patients Lysy et al8 Auvin et al9 Jensen et al10 Engels et al7 Stratton et al6 Cytogenetic Del
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