Genes (Dec 2021)
Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly
- Mateusz Dawidziuk,
- Tomasz Gambin,
- Ewelina Bukowska-Olech,
- Dorota Antczak-Marach,
- Magdalena Badura-Stronka,
- Piotr Buda,
- Edyta Budzynska,
- Jennifer Castaneda,
- Tatiana Chilarska,
- Elzbieta Czyzyk,
- Anna Eckersdorf-Mastalerz,
- Jolanta Fijak-Moskal,
- Dorota Gieruszczak-Bialek,
- Ewelina Glodek-Brzozowska,
- Alicja Goszczanska-Ciuchta,
- Malgorzata Grzeszykowska-Podymniak,
- Barbara Gurda,
- Anna Jakubiuk-Tomaszuk,
- Ewa Jamroz,
- Magdalena Janeczko,
- Dominika Jedlińska-Pijanowska,
- Marta Jurek,
- Dagmara Karolewska,
- Adela Kazmierczak,
- Teresa Kleist,
- Iwona Kochanowska,
- Malgorzata Krajewska-Walasek,
- Katarzyna Kufel,
- Anna Kutkowska-Kaźmierczak,
- Agata Lipiec,
- Dorota Maksym-Gasiorek,
- Anna Materna-Kiryluk,
- Hanna Mazurkiewicz,
- Michał Milewski,
- Tatsiana Pavina-Guglas,
- Aleksandra Pietrzyk,
- Renata Posmyk,
- Antoni Pyrkosz,
- Mariola Rudzka-Dybala,
- Ryszard Slezak,
- Marzena Wisniewska,
- Zofia Zalewska-Miszkurka,
- Elzbieta Szczepanik,
- Ewa Obersztyn,
- Monika Bekiesinska-Figatowska,
- Pawel Gawlinski,
- Wojciech Wiszniewski
Affiliations
- Mateusz Dawidziuk
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Tomasz Gambin
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Ewelina Bukowska-Olech
- Department of Medical Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
- Dorota Antczak-Marach
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Magdalena Badura-Stronka
- Department of Medical Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
- Piotr Buda
- Department of Pediatrics, Nutrition, and Metabolic Diseases, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
- Edyta Budzynska
- Department of Clinical Genetics, Central Clinical Hospital, Medical University of Lodz, 92-213 Lodz, Poland
- Jennifer Castaneda
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Tatiana Chilarska
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland
- Elzbieta Czyzyk
- Clinical Department of Child Neurology, Clinical Central Hospital No. 2 in Rzeszow, 35-301 Rzeszow, Poland
- Anna Eckersdorf-Mastalerz
- Department of Clinical Genetics, Central Clinical Hospital, Medical University of Lodz, 92-213 Lodz, Poland
- Jolanta Fijak-Moskal
- Department of Medical Genetics, Jagiellonian University Medical College, 30-663 Krakow, Poland
- Dorota Gieruszczak-Bialek
- Department of Paediatrics, Medical University of Warsaw, 01-184 Warsaw, Poland
- Ewelina Glodek-Brzozowska
- Clinical Department of Child Neurology, Clinical Central Hospital No. 2 in Rzeszow, 35-301 Rzeszow, Poland
- Alicja Goszczanska-Ciuchta
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Malgorzata Grzeszykowska-Podymniak
- Department of Nephrology, Kidney Transplantation and Hypertension, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
- Barbara Gurda
- Department of Developmental Neurology, Poznan University of Medical Sciences, 60-355 Poznan, Poland
- Anna Jakubiuk-Tomaszuk
- Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok, 15-274 Bialystok, Poland
- Ewa Jamroz
- Department of Pediatric and Neurology of Developmental Age, Saint John Paul II Upper Silesian Child Health Centre, The Independent Public Clinical Hospital No. 6 of the Medical University of Silesia, 40-055 Katowice, Poland
- Magdalena Janeczko
- Department of Genetics, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland
- Dominika Jedlińska-Pijanowska
- Department of Neonatology and Neonatal Intensive Care, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
- Marta Jurek
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Dagmara Karolewska
- Specialist Mother and Child Hospital Complex in Poznan, 61-825 Poznan, Poland
- Adela Kazmierczak
- Independent Public Healthcare Center, Department of Pediatric Neurology, Multidisciplinary Hospital, 67-100 Nowa Sol, Poland
- Teresa Kleist
- Department of Pediatric Neurology Neurological Outpatient Clinic for Children, Municipal Hospital Complex, 41-500 Chorzow, Poland
- Iwona Kochanowska
- Individual Medical Practice in Pediatric Neurology, 70-592 Szczecin, Poland
- Malgorzata Krajewska-Walasek
- Department of Medical Genetics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
- Katarzyna Kufel
- Department of Neonatal and Intensive Care, Medical University of Warsaw, 01-184 Warsaw, Poland
- Anna Kutkowska-Kaźmierczak
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Agata Lipiec
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Dorota Maksym-Gasiorek
- Department of Neonatology, Neonatal Pathology and Intensive Care, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
- Anna Materna-Kiryluk
- Department of Medical Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
- Hanna Mazurkiewicz
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Michał Milewski
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Tatsiana Pavina-Guglas
- Department of Neonatology, Neonatal Pathology and Intensive Care, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
- Aleksandra Pietrzyk
- Department of Genetics and Pathomorphology, Faculty of Medicine and Health Sciences, University of Zielona Gora, 65-046 Zielona Gora, Poland
- Renata Posmyk
- Department of Clinical Genetics, Medical University of Bialystok, 15-089 Bialystok, Poland
- Antoni Pyrkosz
- Department of Medical Genetics, University of Rzeszow, 35-959 Rzeszow, Poland
- Mariola Rudzka-Dybala
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Ryszard Slezak
- Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Marzena Wisniewska
- Department of Medical Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
- Zofia Zalewska-Miszkurka
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Elzbieta Szczepanik
- Clinic of Paediatric Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland
- Ewa Obersztyn
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Monika Bekiesinska-Figatowska
- Department of Diagnostic Imaging, Institute of Mother and Child, 01-211 Warsaw, Poland
- Pawel Gawlinski
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- Wojciech Wiszniewski
- Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
- DOI
- https://doi.org/10.3390/genes12122014
- Journal volume & issue
-
Vol. 12,
no. 12
p. 2014
Abstract
Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.
Keywords