Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy Tamar.

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Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy Tamar Harel, Gozde Yesil, Yavuz Bayram, Zeynep Coban-Akdemir, Wu-Lin Charng, Ender Karaca, Ali Al Asmari, Mohammad K. Eldomery, Jill V. Hunter, Shalini N. Jhangiani, Jill A. Rosenfeld, Davut Pehlivan, Ayman W. El-Hattab, Mohammed A. Saleh, Charles A. LeDuc, Donna Muzny, Eric Boerwinkle, Richard A. Gibbs, Wendy K. Chung, Yaping Yang, John W. Belmont, James R. Lupski The American Journal of Human Genetics Volume 98, Issue 3, Pages 562-570 (March 2016) DOI: 10.1016/j.ajhg.2016.01.011 Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Sanger Validation and Segregation of the Identified Variants (A) Family 1. (B) Family 2. Note the consanguinity. (C) Family 3. Note the consanguinity. (D) Family 4. Segregation of the monoallelic variant in EMC1 in individual II-6 demonstrates the variant in the proband but not in his parents, consistent with a de novo event. (E–G) Evolutionary conservation of the altered amino acid residue at positions 82 (E), 868 (F), and 471 (G). (H) Depiction of the conserved domains of EMC1 and location of the variants identified in the four families. The American Journal of Human Genetics 2016 98, 562-570DOI: (10.1016/j.ajhg.2016.01.011) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 2 Facial Features and Midsagittal Brain MRI Sections of Affected Individuals (A–L) Front and profile photographs of affected individuals from families 1–3 (A–I) and T1-weighted sagittal images (K–L) indicate progressive cerebellar atrophy, atrophic corpus callosum, and diminished cerebral white matter in family 1, as compared to the control individual (J). Thick arrow points to cerebellum vermis; thin arrow indicates corpus callosum. (M–P) T1-weighted (M–O) and T2-weighted (P) sagittal images indicate cerebellar atrophy, cerebral atrophy, and a thin foreshortened corpus callosum in affected individuals of family 2. (Q) Atrophy of the superior cerebellar vermis and a foreshortened corpus callosum in family 3. (R and S) Progressive cerebellar atrophy, mild cerebral atrophy, and foreshortened corpus callosum in family 4. Identifiers refer to pedigree numbers in Figure 1. The American Journal of Human Genetics 2016 98, 562-570DOI: (10.1016/j.ajhg.2016.01.011) Copyright © 2016 The American Society of Human Genetics Terms and Conditions