Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly Julie Jerber, Maha S. Zaki, Jumana.

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Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly Julie Jerber, Maha S. Zaki, Jumana Y. Al-Aama, Rasim Ozgur Rosti, Tawfeg Ben-Omran, Esra Dikoglu, Jennifer L. Silhavy, Caner Caglar, Damir Musaev, Beate Albrecht, Kevin P. Campbell, Tobias Willer, Mariam Almuriekhi, Ahmet Okay Çağlayan, Jiri Vajsar, Kaya Bilgüvar, Gonul Ogur, Rami Abou Jamra, Murat Günel, Joseph G. Gleeson The American Journal of Human Genetics Volume 99, Issue 5, Pages 1181-1189 (November 2016) DOI: 10.1016/j.ajhg.2016.09.007 Copyright © 2016 Terms and Conditions

Figure 1 TMTC3 Is Mutated in COB Brain Malformation (A) Whole-exome sequencing results for 25 unique families. POMT2 and POMGNT1 mutations were found in one and five and families, respectively, and LAMB1 mutations were found in two families. Six unique probands displayed mutations in TMTC3 (dark green). In one-third of the affected individuals, no causative variant could be identified. (B) TMTC3, located on chromosome 12, contains 14 exons (blocks), 13 of which are coding. Variants found in individuals are indicated in red (compound heterozygous above and homozygous below the gene). Scale bar represents 20 kb. (C) TMTC3 (UniProt: Q6ZXV5) has 914 amino acids, 9 transmembrane domains (pink), and 10 TPRs (purple). Variants are indicated in black (compound heterozygous above and homozygous below the protein). (D) Clustal alignment with multiple species shows conservation of the altered amino acids for the two missense variants. Asterisks indicate amino acids conserved in all noted species, and dots represent amino acid variants in at least one species. The American Journal of Human Genetics 2016 99, 1181-1189DOI: (10.1016/j.ajhg.2016.09.007) Copyright © 2016 Terms and Conditions

Figure 2 Family Pedigrees and Brain MRI of Individuals with TMTC3 Variants (A) Pedigrees harboring biallelic damaged variants in TMTC3. Double bars indicate consanguinity, and filled symbols represent affected individuals. (B) Sagittal MRI (upper panel) showing hypoplasia of the corpus callosum (red arrow in B2, B3, and B5), hypoplastic brainstem (yellow arrowhead in B2–B4), cerebellum (yellow star in B3), or dysplastic cerebellum (yellow star in B4 and B5). Note the occipital meningocele (red asterisk in B2). Axial MRI (lower panel) reveals COB with heterotopic neurons (red arrow in B2′, B3′, B5′, and B6’). Ventriculomegaly was also observed in most individuals. The American Journal of Human Genetics 2016 99, 1181-1189DOI: (10.1016/j.ajhg.2016.09.007) Copyright © 2016 Terms and Conditions