Kimberly A. Aldinger, Stephen J. Mosca, Martine Tétreault, Jennifer C

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Mutations in LAMA1 Cause Cerebellar Dysplasia and Cysts with and without Retinal Dystrophy Kimberly A. Aldinger, Stephen J. Mosca, Martine Tétreault, Jennifer C. Dempsey, Gisele E. Ishak, Taila Hartley, Ian G. Phelps, Ryan E. Lamont, Diana R. O’Day, Donald Basel, Karen W. Gripp, Laura Baker, Mark J. Stephan, Francois P. Bernier, Kym M. Boycott, Jacek Majewski, Jillian S. Parboosingh, A. Micheil Innes, Dan Doherty The American Journal of Human Genetics Volume 95, Issue 2, Pages 227-234 (August 2014) DOI: 10.1016/j.ajhg.2014.07.007 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutation Identification in Individuals with CDC (A) Homozygosity mapping in CA0035 identified several regions of homozygosity (red) across the genome. Homozygous regions on chromosome 18 are indicated below the genome-wide mapping. An arrowhead below the chromosome 18 ideogram indicates the location of LAMA1. (B) Pedigree diagrams showing segregation analysis for five families. (C) LAMA1 is composed of 63 exons that span chr18: 6,941,743–7,117,813 (UCSC Genome Browser hg19) and encode protein-coding sequence. Arrows indicate the locations of ten different mutations identified in five families. The horizontal red bar represents a deletion spanning LAMA1 exons 4–11. (D) The splice-site mutation (designated red in C) in UW154-3 results in skipping of exon 45. Total RNA was isolated from fibroblasts with the RNeasy Mini Kit (QIAGEN) and transcribed into cDNA with the SuperScript III First-Strand System and random hexamer primers (LifeTechnologies). RT-PCR was performed under standard conditions with forward primers in exons 43 and 44 and reverse primers in exons 45 and 46 (sequences are available upon request). Primers in exons 44 and 45 generated a 170 bp amplicon in cDNA from two unrelated, unaffected control fibroblasts but minimal product in cDNA from UW154-3. Primers in exons 43 and 46 generated a 354 bp amplicon in control cells and a 199 bp product in UW154-3. Sanger sequencing of this product revealed that exon 43 is spliced to exon 45 in UW154-3 (data not shown). The horizontal arrows indicate primer positions. The red arrow indicates the location of the splice-site mutation in intron 44. “L” indicates the ladder lane, “C1” and “C2” indicate the two control samples, and “P” indicates individual UW154-3. The expected size and exon composition of the respective products are indicated to the right of the gel. The American Journal of Human Genetics 2014 95, 227-234DOI: (10.1016/j.ajhg.2014.07.007) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain and Eye Imaging Findings in Affected Individuals with LAMA1 Mutations (A–E) Individual CA0035 has cerebellar cysts (arrowheads in A), superior cerebellar dysplasia (arrow in B) and large globes (B), elevated and splayed superior cerebellar peduncles (arrowheads in C), an enlarged fourth ventricle (A and D), and patchy increased T2/FLAIR (asterisks in E). The periventricular heterotopia (arrowhead in E) is atypical. (F–J) Similar findings in UW154-3 include cerebellar cysts (arrowhead in F), superior cerebellar dysplasia (arrowhead in G) and large globes (G), elevated and splayed superior cerebellar peduncles (arrowheads in H), an enlarged fourth ventricle (F and I), and patchy increased T2/FLAIR (asterisks in E). In addition, UW154-3 has partial absence of the corpus callosum (bracket in I) and septum pellucidum (plus sign in J). (K–N) UW163-3 has only superior cerebellar dysplasia (arrow in L) and patchy increased T2/FLAIR (asterisks in O), but no cerebellar cysts (K). The superior cerebellar peduncles (M) and the fourth ventricle (K and N) are normal. The American Journal of Human Genetics 2014 95, 227-234DOI: (10.1016/j.ajhg.2014.07.007) Copyright © 2014 The American Society of Human Genetics Terms and Conditions