GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome Amy J. LaCroix, Deborah Stabley, Rebecca.

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GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome Amy J. LaCroix, Deborah Stabley, Rebecca Sahraoui, Margaret P. Adam, Michele Mehaffey, Kelly Kernan, Candace T. Myers, Carrie Fagerstrom, George Anadiotis, Yassmine M. Akkari, Katherine M. Robbins, Karen W. Gripp, Wagner A.R. Baratela, Michael B. Bober, Angela L. Duker, Dan Doherty, Jennifer C. Dempsey, Daniel G. Miller, Martin Kircher, Michael J. Bamshad, Deborah A. Nickerson, Heather C. Mefford, Katia Sol-Church The American Journal of Human Genetics Volume 104, Issue 1, Pages 35-44 (January 2019) DOI: 10.1016/j.ajhg.2018.11.005 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 XYLT1 Exon 1 and Surrounding Region Schematic of XYLT1 (GRCh37/hg19, GenBank: NM_022166) exon 1 and surrounding region, noting the region upstream previously described as XYLT1-238, which contains the GGC repeat region; genomic coordinates notated. Methylation-specific PCR was performed on the bracketed segment of exon 1, which includes 48 CpG sites. The American Journal of Human Genetics 2019 104, 35-44DOI: (10.1016/j.ajhg.2018.11.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 BSS Cohort (A) Pedigrees of 10 families with 12 affected individuals included in this study. XYLT1 variants are noted for those individuals tested. CH3, methylated allele; del, 16p13 deletion; ∗, individual underwent exome sequencing; hmz, homozygous. (B) Proband 06-1 as an infant. (C) Proband 04-1 at 9 years of age. Dysmorphic features include flat midface, depressed nasal bridge, epicanthal folds. The American Journal of Human Genetics 2019 104, 35-44DOI: (10.1016/j.ajhg.2018.11.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 Methylated Alleles Are Not Transcribed (A) Sequence analysis of MS-PCR product from bisulfite-treated genomic DNA (top) of individual 02-1 confirms that the XYLT1 point mutation (c.319G>T) is located on the unmethylated allele in genomic DNA. CpG sites are notated (∗). Fibroblast cDNA sequence (bottom) confirms that only the unmethylated allele is transcribed. (B) RT-PCR of fibroblast cDNA from 04-1 shows that transcription of exon 1-3 is absent and levels of shortened transcripts that begin downstream are reduced compared to the control. (C) Sashimi Plot of RNA-seq data for 04-1 shows exon 1 is not transcribed and the exon 1-2 junction is absent. Overall transcription levels are severely reduced compared to the control. The American Journal of Human Genetics 2019 104, 35-44DOI: (10.1016/j.ajhg.2018.11.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 4 Southern Blot of Four Affected Individuals and Available Family Members The expected wild-type fragment (2,800 bp) encompasses exon 1 and surrounding DNA including XYLT1-238. For each individual with one or two methylated alleles, a fragment 300–2,500 bp larger than expected was detected. Individual 07-4 has two methylated alleles; 04-1 and 06-1 each have one methylated and one deleted allele, and 02-1 is heterozygous for methylation. In families 07 and 04, there is further expansion when transmitted from unaffected mother to affected child. Fragments that are >400 bp larger than wild-type exhibit instability in somatic cells as indicated by the non-distinct bands seen; particularly in 02-1 and 04-1. Each panel is from the same Southern blot but with different exposure times (panel 1, 4 day; panel 2, 24 hr; panel 3, 4 day). The American Journal of Human Genetics 2019 104, 35-44DOI: (10.1016/j.ajhg.2018.11.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions