Media type: E-Article Title: Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions Contributor: Krutzke, Sophia K.; Engels, Hartmut; Hofmann, Andrea; Schumann, Madita M.; Cremer, Kirsten; Zink, Alexander M.; Hilger, Alina; Ludwig, Michael; Gembruch, Ulrich; Reutter, Heiko; Merz, Waltraut M. imprint: Wiley, 2016 Published in: Birth Defects Research Part A: Clinical and Molecular Teratology Language: English DOI: 10.1002/bdra.23458 ISSN: 1542-0752; 1542-0760 Keywords: Developmental Biology ; Embryology ; General Medicine ; Pediatrics, Perinatology and Child Health Origination: Footnote: Description: <jats:sec><jats:title>BACKGROUND</jats:title><jats:p>For the majority of congenital brain malformations, the underlying cause remains unknown. Recent studies have implicated rare copy number variations (CNVs) in their etiology.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Here, we used array‐based molecular karyotyping to search for causative CNVs in 33 fetuses of terminated pregnancies with prenatally detected brain malformations and additional extracerebral anomalies.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>In 11 fetuses, we identified 15 CNVs (0.08 Mb to 29.59 Mb), comprising four duplications and eleven deletions. All larger CNVs (> 5 Mb) had also been detected by prenatal conventional karyotyping. None of these CNVs was present in our 1307 healthy in‐house controls (frequency < 0.0008). Among these CNVs, we prioritized six chromosomal regions (1q25.1, 5q35.1, 6q25.3‐qter, 11p14.3, 15q11.2‐q13.1, 18q21.1) due to their previous association with human brain malformations or owing to the presence of a single gene expressed in human brain. Prioritized genes within these regions were <jats:italic>UBTD2, SKA1, SVIP</jats:italic>, and, most convincingly, <jats:italic>GPR52</jats:italic>. However, re‐sequencing of <jats:italic>GPR52</jats:italic> in 100 samples from fetuses with brain malformations or patients with intellectual disability and brain malformations revealed no disease‐causing mutation.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p>Our study suggests chromosomal regions 1q25.1, 5q35.1, 6q25.3‐qter, 11p14.3, 15q11.2‐q13.1, and 18q21.1 to be involved in human brain development. Within three of these regions, we suggest <jats:italic>UBTD2, GPR52</jats:italic>, and <jats:italic>SKA1</jats:italic> as possible candidate genes. Because the overall detection rate of array‐based molecular karyotyping was slightly higher (23%) than that of conventional prenatal karyotyping (20%), we suggest it's use for prenatal diagnostic testing in fetuses with nonisolated brain malformations. Birth Defects Research (Part A) 106:16–26, 2016. © 2015 Wiley Periodicals, Inc.</jats:p></jats:sec>