@article {614, title = {Analysis of 17 genes detects mutations in 81\% of 811 patients with lissencephaly.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 11}, pages = {1354-1364}, abstract = {

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.

RESULTS: The overall mutation frequency in the entire cohort was 81\%. LIS1 accounted for 40\% of patients, followed by DCX (23\%), TUBA1A (5\%), and DYNC1H1 (3\%). Other genes accounted for 1\% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.

CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

}, keywords = {Brain, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Lissencephaly, Male, Mutation, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2018.8}, author = {Di Donato, Nataliya and Timms, Andrew E and Aldinger, Kimberly A and Mirzaa, Ghayda M and Bennett, James T and Collins, Sarah and Olds, Carissa and Mei, Davide and Chiari, Sara and Carvill, Gemma and Myers, Candace T and Rivi{\`e}re, Jean-Baptiste and Zaki, Maha S and Gleeson, Joseph G and Rump, Andreas and Conti, Valerio and Parrini, Elena and Ross, M Elizabeth and Ledbetter, David H and Guerrini, Renzo and Dobyns, William B} } @article {273, title = {Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 01}, pages = {2888-900}, abstract = {

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80\% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for \~{}5\% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Cohort Studies, Cranial Fontanelles, De Lange Syndrome, Eye Abnormalities, Female, Genes, X-Linked, Histone Deacetylases, Humans, Hypertelorism, Infant, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Repressor Proteins, Sequence Alignment}, issn = {1460-2083}, doi = {10.1093/hmg/ddu002}, author = {Kaiser, Frank J and Ansari, Morad and Braunholz, Diana and Concepci{\'o}n Gil-Rodr{\'\i}guez, Mar{\'\i}a and Decroos, Christophe and Wilde, Jonathan J and Fincher, Christopher T and Kaur, Maninder and Bando, Masashige and Amor, David J and Atwal, Paldeep S and Bahlo, Melanie and Bowman, Christine M and Bradley, Jacquelyn J and Brunner, Han G and Clark, Dinah and Del Campo, Miguel and Di Donato, Nataliya and Diakumis, Peter and Dubbs, Holly and Dyment, David A and Eckhold, Juliane and Ernst, Sarah and Ferreira, Jose C and Francey, Lauren J and Gehlken, Ulrike and Guill{\'e}n-Navarro, Encarna and Gyftodimou, Yolanda and Hall, Bryan D and Hennekam, Raoul and Hudgins, Louanne and Hullings, Melanie and Hunter, Jennifer M and Yntema, Helger and Innes, A Micheil and Kline, Antonie D and Krumina, Zita and Lee, Hane and Leppig, Kathleen and Lynch, Sally Ann and Mallozzi, Mark B and Mannini, Linda and McKee, Shane and Mehta, Sarju G and Micule, Ieva and Mohammed, Shehla and Moran, Ellen and Mortier, Geert R and Moser, Joe-Ann S and Noon, Sarah E and Nozaki, Naohito and Nunes, Luis and Pappas, John G and Penney, Lynette S and P{\'e}rez-Ayt{\'e}s, Antonio and Petersen, Michael B and Puisac, Beatriz and Revencu, Nicole and Roeder, Elizabeth and Saitta, Sulagna and Scheuerle, Angela E and Schindeler, Karen L and Siu, Victoria M and Stark, Zornitza and Strom, Samuel P and Thiese, Heidi and Vater, Inga and Willems, Patrick and Williamson, Kathleen and Wilson, Louise C and Hakonarson, Hakon and Quintero-Rivera, Fabiola and Wierzba, Jolanta and Musio, Antonio and Gillessen-Kaesbach, Gabriele and Ramos, Feliciano J and Jackson, Laird G and Shirahige, Katsuhiko and Pi{\'e}, Juan and Christianson, David W and Krantz, Ian D and FitzPatrick, David R and Deardorff, Matthew A} }