Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss Prasanthi Namburi,

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Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss Prasanthi Namburi, Rinki Ratnapriya, Samer Khateb, Csilla H. Lazar, Yael Kinarty, Alexey Obolensky, Inbar Erdinest, Devorah Marks- Ohana, Eran Pras, Tamar Ben-Yosef, Hadas Newman, Menachem Gross, Anand Swaroop, Eyal Banin, Dror Sharon The American Journal of Human Genetics Volume 99, Issue 3, Pages 777-784 (September 2016) DOI: 10.1016/j.ajhg.2016.07.010 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 CEP78 Genomic Arrangement and Mutation Identification (A) Pedigree of families with CEP78 mutation. Filled symbols designate affected individuals. Red arrows represent index case. Family number is depicted above each family tree and individual number below each symbol. The CEP78 genotype of recruited individuals is depicted below the individual number: M1, c.893-1G>A; M2, c.534delT; +, wild-type allele. Genomic DNA was isolated using Maxwell® 16 Blood DNA Purification Kit (Promega). (B) The chromosomal region harboring CEP78 at chromosome 9. (C) Schematic representation of three different transcripts of CEP78 and the location of the identified mutations (pink dashed line). Black rectangles represent constitutive exons and red represent an alternatively-spliced exon. (D) Exome sequence alignment of the c.893-1G>A mutation region in MOL0679 III:1. WES analysis was performed using Nextera Rapid Capture Expanded Exome kit on a HiSeq2500 platform (Illumina). Mapping to the human reference sequence (hg19, GRCH37) was performed using BWA, variants were called using GATK pipeline, and annotation of variants was done with ANNOVAR. Only a representative set of reads is depicted. (E) Chromatograms of a homozygous wild-type (top), a heterozygous unaffected family member (middle), and a homozygous affected individual (bottom). The American Journal of Human Genetics 2016 99, 777-784DOI: (10.1016/j.ajhg.2016.07.010) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Imaging of Individuals with Bi-allelic CEP78 Variants Ordered by Age (A–C) TB365 II:1 (38 years). (D–F) MOL0679 III:1 (44 years), (G–I) TB279 II:1 (47 years), (J–L) MOL0679 III:2 (47 years), and (M–O) MOL0773 II:1 (48 years). Color fundus photos of the posterior pole (left panels) and Optos wide-angle images (middle panels) show mild macular RPE changes, ring of atrophy along the vascular arcades surrounding the macula, and subtle peripheral salt and pepper changes with no BSPs. The findings are more clearly evident on fundus auto fluorescence (FAF) imaging (right panels) showing hypo-autofluorescence along the vascular arcades with a macular hyper-autofluorescent ring. The American Journal of Human Genetics 2016 99, 777-784DOI: (10.1016/j.ajhg.2016.07.010) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 CEP78 RNA Expression Analysis (A) The effect of the c.893-1G>A mutation on CEP78 mRNA splicing in blood leukocytes. RT-PCR analysis was performed on cDNA samples of a homozygous individual (MOL0773 II:1, lane 1) and a WT individual (lane 2). Lane 3 includes a negative control. M represents a 0.1–10 kb DNA ladder (100, 300, and 500 bp bands are indicated). The schematic drawing on the left represents the amplicons of the WT and mutant alleles as verified by direct Sanger sequencing. Total RNA was isolated using the QIAamp RNA Blood Mini Kit (QIAGEN) and RT-PCR was performed using Verso cDNA Kit (Thermo Scientific). (B) RNaseq data extracted from 11 postmortem human retinal samples. The FPKM (fragments per kilobase of transcript per million mapped fragments) of the three identified CEP78 transcripts is depicted. RNA was isolated with TRIzol LS and assessed using Bioanalyzer RNA 6000 Pico assay (Agilent Technologies). Strand-specific libraries were constructed with 20–100 ng of total RNA using TruSeq RNA Sample Prep Kit-v2 (Illumina). Reads were aligned to the Ensembl v73 transcriptome annotation using Bowtie2 and transcript quantitation was performed with eXpress. (C) Expression level of CEP78 versus PGM1 (MIM 171900) in different human tissues (Clontech; cat #636643, lot No. 8101369A) using two sets of primers located in exons 6 through 9 and exons 14 through 16 and designed to amplify all three transcripts. Lane 1, bone marrow; 2, brain (whole); 3, fetal brain; 4, fetal liver; 5, heart; 6, kidney; 7, liver; 8, lung; 9, placenta; 10, prostate; 11, spleen; 12, thymus; 13, uterus; 14, small intestine; 15, spinal cord; 16, stomach; 17, retina; 18, negative control; and M, 0.1–10 kb DNA ladder. (D) Expression of Cep78 and Pgk1 in the mouse retina (at the age of E14 [lane 1], P0 [lane 2], and P30 [lane 3]) and inner ear at P30 (lane 4). Negative controls are shown in lanes 5. (E) RNA-seq analysis of Cep78 in flow-sorted photoreceptors isolated from WT retina (blue) versus the cone-enriched Nrl-KO retina (red). GFP-positive cells were isolated from Nrlp-GFP or Nrlp-GFP;Nrl-KO mice retina at different postnatal stages of development by fluorescence-activated cell sorting (FACS).30 The American Journal of Human Genetics 2016 99, 777-784DOI: (10.1016/j.ajhg.2016.07.010) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 CEP78 Immunolocalization in the Human Retina (A and B) Low-magnification images (20X) of control retina showing DAPI staining (B) and double staining (A) with the antibodies anti-CEP78 (HPA048846 from Sigma at a final concentration of 1:200) in green and anti-S-opsin (AB5407 from Chemicon International, Temecula; at a final concentration of 1:75) in red. The secondary antibodies were DyLight 488 donkey anti-rabbit and rhodamine red-X-conjugated donkey anti-goat IgG respectively (both in 1:250 dilution from Jackson Immuno Research Laboratories). (C) Higher magnification of the photoreceptor-RPE region. Note dense staining of the cone inner segment and the base of the rod inner segment (original magnification 40X with digital zoom). GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; IS, inner segments of photoreceptors; OS, outer segments of photoreceptors; RPE, retinal pigment epithelium layer. The American Journal of Human Genetics 2016 99, 777-784DOI: (10.1016/j.ajhg.2016.07.010) Copyright © 2016 American Society of Human Genetics Terms and Conditions