Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21
Authors: Elena Cicchini
Maria Chiara Pelleri
Marco Seri
Pamela Magini
Lorenza Vitale
Guido Cocchi
Teresa Mattina
Chiara Locatelli
Lisbeth Tranebjaerg
Pierluigi Strippoli
Michael B Petersen
Maria Caracausi
Francesca Antonaros
Allison Piovesan
Journal: Molecular Genetics & Genomic Medicine (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Down syndrome; computational biology; highly restricted Down syndrome critical region; human chromosome 21; intellectual disability
Affiliations: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology University of Bologna Bologna (BO) Italy, Department of Genetics Aalborg University Hospital Aalborg Denmark, Department of Clinical Genetics Aalborg University Aalborg Denmark, Department of Clinical Genetics/Rigshospitalet The Kennedy Centre Glostrup Denmark, University of Copenhagen, Institute of Clinical Medicine, The Panum Institute Copenhagen N Denmark, Department of Pediatrics Medical Genetics University of Catania Italy, Medical Genetics Unit St. Orsola‐Malpighi Polyclinic Bologna (BO) Italy, Neonatology Unit St. Orsola‐Malpighi Polyclinic Bologna (BO) Italy, Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC) St. Orsola‐Malpighi Polyclinic, University of Bologna Bologna (BO) Italy, Neonatology Unit, Department of Medical and Surgical Sciences (DIMEC) St. Orsola‐Malpighi Polyclinic, University of Bologna Bologna (BO) Italy

Abstract:  Background: Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype-phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR-DSCR limits could prospectively be confirmed and possibly refined. Methods: Hsa21 partial duplications of three PT21 subjects were refined by adding array-based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map. Results: The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR-DSCR, on distal 21q22.13 sub-band, only in DS subjects and not in non-DS individuals. No documented exception to the HR-DSCR model was found. Conclusions: The findings presented here further support the association of the HR-DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR-DSCR and functionally associated to the critical manifestations of DS. 

Retracted: No

PubPeer comments:
 Because the 34-kb highly restricted DSCR (HR-DSCR) on distal 21q22.13 identified by Pelleri et al. (2016) is devoid of protein-coding genes, these authors invoke the remarkable pleiotropy of microRNA genes to suggest that one (or some) still unknown microRNA located therein is a crucial contributor to the DS phenotype. In this subsequent paper (2019), Pelleri et al. refer to other researchers work not only to support the microRNA conjecture but also to highlight that a recently identified new intron in the KCNJ6 gene encompasses the whole 34-kb critical region. It seems rather obvious that the pleiotropy of microRNAs fits well the concept of amplified developmental instability advanced by Shapiro (who was elaborating on classical Waddington s views) to explain the phenotype of patients with trisomy 21 or other aneuploidies (Ann Hum Genet 38: 429-37, 1975), a concept that Pelleri et al. overlook in their papers. It is also unfortunate that these authors (2016) cite only once to Shapiro and for the wrong reason, namely, to backup the existence of a  Down syndrome minimal region . This citation is clearly out of context insofar as Shapiro has always militated against the notion of a critical or minimal DS region (Am J Med Genet 33: 146-50, 1989; Hum Genet 99: 421-3, 1997). ,