Supplemental Data. Biallelic Variants in CNPY3, Encoding. an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy
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1 The American Journal of Human Genetics, Volume 102 Supplemental Data Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy Hiroki Mutoh, Mitsuhiro Kato, Tenpei Akita, Takuma Shibata, Hiroyuki Wakamoto, Hiroko Ikeda, Hiroki Kitaura, Kazushi Aoto, Mitsuko Nakashima, Tianying Wang, Chihiro Ohba, Satoko Miyatake, Noriko Miyake, Akiyoshi Kakita, Kensuke Miyake, Atsuo Fukuda, Naomichi Matsumoto, and Hirotomo Saitsu
2 Supplemental Note: Case report Individual 1 This female individual was an elder sister of individual 2 (Figure 1A). The pregnancy was uneventful, and she was delivered spontaneously with no asphyxia at 39 weeks of gestation. Her birth weight was 2800 g [-0.2 standard deviation (SD)]. At 3 months of age, she experienced epileptic spasms and electroencephalography (EEG) revealed hypsarrhythmia, leading to a diagnosis of West syndrome. Her seizures disappeared with a combination of valproic acid (VPA) and ethyl loflazepate. At 3 years 2 months, she exhibited focal impaired awareness seizures, which responded well to a combination of clonazepam (CZP) and zonisamide. At 4 years of age, myoclonic seizures appeared and occurred five times per week despite the administration of antiepileptic medications, including clobazam and topiramate. Her interictal EEG at 10 years of age showed fast waves and diffuse sharp- and slow-wave complexes (Figure S3B). Brain MRI at 7 years showed mild brain atrophy and malrotation of the left hippocampus (Figure 2A and 2B). Head computed tomography (CT) at 11 years of age showed diffuse atrophic changes in the brain. Her psychomotor development was severely delayed. At 14 years of age, her body height was 135 cm (-4.2 SD), body weight was 27.6 kg (-2.9 SD), and head circumference was 52.0 cm (+0.8 SD). She showed spastic quadriplegia and was unable to roll over. She had no meaningful words and was unable to communicate with others. Individual 2 This female individual was a younger sister of individual 1 (Figure 1A). Her parents were healthy and non-consanguineous. The pregnancy was uneventful, and she was
3 delivered spontaneously with no asphyxia at 37 weeks of gestation. Her birth weight was 2510 g (-0.3 SD). She experienced epileptic spasms, and EEG revealed modified hypsarrhythmia, leading to a diagnosis of West syndrome at 4 months of age. Her EEG at 8 years showed fast waves associated with tonic seizures and diffuse sharp- and slowwave complexes in an interictal state (Figure S3C). Her seizures temporarily disappeared with a combination of VPA and CZP, although myoclonic seizures, refractory to drugs, occurred at 14 months of age. Brain MRI at 4 years showed mild brain atrophy and malrotation of the right hippocampus (Figure 2C and 2D). Head CT at 9 years of age showed diffuse atrophic changes in the brain. Her psychomotor development was severely delayed. At 12 years of age, her body height was 125 cm (- 4.6 SD), body weight was 28.6 kg (-2.0 SD), and head circumference was 51.0 cm (+0.2 SD). She displayed spastic quadriplegia and was unable to roll over. She had no meaningful words and was unable to communicate with others. Individual 3 This male individual was the first child born to second cousins, who were healthy Japanese parents (Figure 1A). The pregnancy was uneventful, and he was delivered spontaneously at 40 weeks of gestation. His birth weight was 2704 g (-1.2 SD). Although he had no asphyxia, he suffered from pneumonia soon after birth, and his condition worsened at 5 days of age, with apnea and feeding difficulties. He experienced tonic seizures and erratic myoclonus at 1 month of age. Multiple drugs, including vitamin B6, phenobarbital, VPA, diazepam, and carbamazepine, were ineffective for stopping his seizures. His EEG showed a suppression burst pattern at 3 months, and he was diagnosed with early myoclonic encephalopathy. He had epileptic
4 spasms, and his EEG findings shifted to hypsarrhythmia at 4 months (Figure S3A). The diagnosis was changed to West syndrome. His brain MRI scans at 1 and 4 months showed diffuse brain atrophy and malrotation of the bilateral hippocampus (Figure 2E and 2F). At 7 months of age, he had 100 epileptic spasms per day in clusters or separately. He had gastroesophageal reflux owing to a hiatal hernia. He showed spasticity of bilateral lower extremities and was unable to roll over. He underwent corpus callosotomy, which reduced his seizure frequency by half for a few weeks. He died at the age of 13 months.
5 Figure S1 Sanger sequencing of CNPY3 variants. Affected individuals with biallelic CNPY3 variants and heterozygous carrier parents of individuals 1 and 2 are clearly displayed on electropherograms.
6 Figure S2 A 20 Mb homozygous stretch on chromosome 6 in individual 3. The copy number and loss of heterozygosity analysis on chromosome 6 were performed using Cytogenetics Whole-Genome 2.7M Array (Affymetrix, Santa Clara, CA) with Chromosome Analysis Suite with NA30 (hg19) annotations. A 20 Mb homozygous stretch lacking heterozygous calls (red box) was identified in individual 3 that was not observed in a control individual. The location of CNPY3 is indicated by an arrow.
7
8 Figure S3 Electroencephalograms (EEGs) of individuals with CNPY3 variants. (A) Awake interictal EEG of individual 3 at age 4 months shows multifocal or diffuse sharp waves or sharp and slow waves and desynchronization for 1 s with irregular slow waves, which is compatible with hypsarrhythmia. (B) Individual 1 at the age of 10 years shows 10-Hz, 300- V parietal-dominant diffuse fast waves for 1 3 s and continuous diffuse sharp- and slow-wave complexes. (C) Individual 2 at age 8 years shows bilateral frontal or frontal-dominant diffuse sharp and slow waves, continuous 1-Hz diffuse sharp and slow waves (not shown), and 9-Hz, 500- V diffuse high-amplitude fast waves for 5 s of tonic seizures elevating both arms in line with fluctuating and fast-wave coupling electrocardiogram followed by diffuse slow waves and desynchronization for several seconds.
9 Figure S4 Histological evaluations of wild-type (WT) and CNPY3 / (knockout, KO) mouse brain. There were no apparent histological abnormalities in the cortex, hippocampus and cerebellum of the KO mice.
10 Figure S5 Enhancement of beta-band power on a resting electroencephalogram (EEG) was not observed in CNPY3 +/ mice. (Left) Averaged power density spectra of EEG traces from Cnpy3 +/+ (black line, n = 8), Cnpy3 +/ (blue line, n = 7), and Cnpy3 / (red line, n = 9) mice. The densities were normalized to the total signal power. (Right) Expanded spectra showing in the left. Data are presented as means ± SEM.
11 Table S1 Summary of the whole exome sequencing analysis of a family with individuals 1 and 2 Individual 1 Individual 2 Father Mother Depth of Coverage a Mean depth %_bases_above %_bases_above Variant filtering Rare nonsynonymous variants b Candidate gene De novo variant 1 (KMT2C) 0 Homozygous variant 1 (IFIT1) 0 Compound heterozygous variants Common in two individuals 3 (TTN, CNPY3 KIAA1551) CNPY3 1 (CNPY3) CNPY3 a Coverage data were calculated against protein coding sequences of RefSeq genes. b Variants that passed GATK hand-filtering, below minor allele frequencies of 1% in GnomeAD East Asian data ( Human Genetic Variation Database ( 2KJPN ( and our in-house control exomes.
12 Table S2 Prediction of the pathogenicity of candidate variants Common in individuals 1 and 2 Gene Inheritance cdna change Amino acid change CNPY3 NM_ CNPY3 NM_ GnomAD MAF SIFT Paternal c.373g>c p.(gly125arg) Polyphen2 HumVar Probably damaging Maternal c.702_720dup p.(ser241glyfs*7) - N/A N/A Mutation Taster Disease causing Disease causing CADD Phred MCAP N/A N/A For individual 1 Gene Inheritance cdna change Amino acid change GnomAD MAF SIFT Polyphen2 HumVar Mutation Taster CADD Phred MCAP KMT2C NM_ IFIT1 NM_ TTN NM_ De novo c.638c>t p.(thr213ile) Paternal and maternal (Homozygous) c.1259a>g p.(asn420ser) 8.94 x Maternal c.7122g>t p.(gln2374his) 4.07 x Probably damaging Benign Probably damaging Disease causing Polymorphism Polymorphism TTN NM_ Paternal c.54293t>c p.(ile18098thr) 3.67 x Benign Disease causing TTN NM_ Paternal c.61490t>c p.(leu20497ser) 9.39 x Benign Polymorphism
13 KIAA1551 NM_ Paternal c.524g>a p.(arg175gln) Probably damaging Polymorphism KIAA1551 NM_ Maternal c.4138g>a p.(gly1380arg) Probably damaging Polymorphism For individual 3 Gene cdna change Amino acid change GnomAD MAF ESE Finder BDGP HSF3.0 CNPY3 NM_ c.495+1g>a - - Score 8.21 disappeared Score 0.87 disappeared Score N/A = not applicable. GnomAD ( SIFT ( scores < 0.05 indicate that substitutions are predicted to be intolerant. PolyPhen-2 ( scores are evaluated as (most probably benign) to (most probably damaging). MutationTaster ( rapid evaluation of DNA sequence alterations. The alterations are classified as disease-causing or polymorphisms. Probability value is shown. ESEfinder 3.0 ( BDGP ( HSF3.0 (
14 Table S3 Comparison of mortality in response to repeated injection of pilocarpine 100 mg/kg at 30-min intervals in Cnpy3 +/+ and Cnpy3 / mice Total number of mice Mortality rate during EEG (2hr) First pilocarpine Second pilocarpine Third pilocarpine Cnpy3 +/+ 7 6/7 0/7 1/7 5/7 Cnpy3 -/- 8 8/8 0/8 1/8 7/8
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