Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome.

Autor: Bestetti I; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20142 Milan, Italy., Crippa M; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20142 Milan, Italy., Sironi A; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20142 Milan, Italy., Tumiatti F; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy., Masciadri M; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy., Smeland MF; Department of Medical Genetics, University Hospital of North Norway, 9019 Tromsø, Norway., Naik S; Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK., Murch O; All Wales Medical Genomics Service, University Hospital of Wales, Cardiff CF14 4XW, UK., Bonati MT; Clinic of Medical Genetics, San Luca Hospital, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy., Spano A; Clinical Pediatric Genetic Unit, Pediatric Clinic, Fondazione MBBM, San Gerardo Hospital, 20900 Monza, Italy., Cattaneo E; Clinical Genetics Unit, Department of Obstetrics and Gynecology, 'V. Buzzi' Children's Hospital, University of Milan, 20142 Milan, Italy., Mariani M; Pediatric Unit, ASST Lariana, 22100 Como, Italy., Gotta F; Clinical Genetics, ASST Cremona, Via Concordia 1, 26100 Cremona, Italy., Crosti F; Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy., Cavalli P; Clinical Genetics, ASST Cremona, Via Concordia 1, 26100 Cremona, Italy., Pantaleoni C; Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20142 Milan, Italy., Natacci F; Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20142 Milan, Italy., Bedeschi MF; Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20142 Milan, Italy., Milani D; Pediatric Highly Intensive Care, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20142 Milan, Italy., Maitz S; Clinical Pediatric Genetic Unit, Pediatric Clinic, Fondazione MBBM, San Gerardo Hospital, 20900 Monza, Italy.; Service of Medical Genetics, Oncologic Institute of Southern Switzerland, EOC, 6900 Lugano, Switzerland., Selicorni A; Pediatric Unit, ASST Lariana, 22100 Como, Italy., Spaccini L; Clinical Genetics Unit, Department of Obstetrics and Gynecology, 'V. Buzzi' Children's Hospital, University of Milan, 20142 Milan, Italy., Peron A; Child Neuropsychiatry Unit-Epilepsy Center, Department of Health Sciences, ASST Santi Paolo e Carlo, San Paolo Hospital, Università Degli Studi di Milano, 20142 Milan, Italy.; Medical Genetics, ASST Santi Paolo e Carlo, San Paolo Hospital, 20142 Milan, Italy.; Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA., Russo S; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy., Larizza L; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy., Low K; University Hospitals Bristol NHS Trust, University of Bristol, Bristol BS1 3NU, UK., Finelli P; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20142 Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20142 Milan, Italy.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 May 25; Vol. 23 (11). Date of Electronic Publication: 2022 May 25.
DOI: 10.3390/ijms23115912
Abstrakt: KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 ( ANKRD11 ) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11 . A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.
Databáze: MEDLINE
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