Abstracts J Investig Med: first published as 10.1136/jim-2021-WRMC on 21 December 2020. Downloaded from Genetics I Purpose of Study Genomic sequencing has identified a growing number of genes associated with developmental brain disorders Concurrent session and revealed the overlapping genetic architecture of autism spectrum disorder (ASD) and intellectual disability (ID). Chil- 8:10 AM dren with ASD are often identified first by psychologists or neurologists and the extent of genetic testing or genetics refer- Friday, January 29, 2021 ral is variable. Applying clinical whole genome sequencing (cWGS) early in the diagnostic process has the potential for timely molecular diagnosis and to circumvent the diagnostic 1 PROSPECTIVE STUDY OF EPILEPSY IN NGLY1 odyssey. Here we report a pilot study of cWGS in a clinical DEFICIENCY cohort of young children with ASD. RJ Levy*, CH Frater, WB Galentine, MR Ruzhnikov. Stanford University School of Medicine, Methods Used Children with ASD and cognitive delays/ID Stanford, CA were referred by neurologists or psychologists at a regional healthcare organization. Medical records were used to classify 10.1136/jim-2021-WRMC.1 probands as 1) ASD/ID or 2) complex ASD (defined as 1 or more major malformations, abnormal head circumference, or Purpose of Study To refine the electroclinical phenotype of dysmorphic features). cWGS was performed using either epilepsy in NGLY1 deficiency via prospective clinical and elec- parent-child trio (n=16) or parent-child-affected sibling (multi- troencephalogram (EEG) findings in an international cohort. plex families; n=3). Variants were classified according to Methods Used We performed prospective phenotyping of 28 ACMG guidelines. Pathogenic/likely pathogenic variants associ- subjects with NGLY1 deficiency via standardized clinician ated with ASD/ID were considered molecular diagnoses while interviews every 4 months of medical, developmental and seiz- variants of uncertain significance were considered candidate ure history. Seizure and medication history was confirmed variants. with prior records. 14 subjects also underwent in-person eval- Summary of Results 19 children (9 females) received cWGS at uations including EEG, obtained via 20 lead standard array. a median age of 4 yrs (range 2.0–7.5 yrs). Six children were Descriptive statistics are provided for the first year of an classified as complex ASD. cWGS identified a molecular diag- ongoing natural history study. nosis in 6 females of which 5 were complex ASD. All molecu- Summary of Results All subjects had typical symptoms including: lar diagnoses were due to rare de novo variants (CSNK2B, global developmental delay and/or intellectual disability, hypo- or DDX3X, LZTR1, MED12, PUM1, SMARCA2). No molecular alacrima, hyperkinetic movement disorder and transient elevation diagnoses were reported for males; 4 males had candidate var- in transaminases. 17/28 (60.7%) had a history of epilepsy, with iants. Three females had medical management changes includ- – mean seizure onset at 37 months (interquartile range 5 60 ing condition-specific surveillance and eligibility for targeted months,range2monthsto19years).Seizuretypesincluded therapy. myoclonic (8/17, 47%), astatic (7/17, 41%), and absence (6/17, Conclusions These preliminary results highlight the contribu- 35%); focal with secondary generalization, tonic, generalized tonic tion of rare de novo variants in children with ASD with cog- clonic, and infantile spasms were also reported. 10/14 (71%) sub- nitive delays, consistent with prior research literature. jects had generalized interictal epileptiform activity on EEG. EEG Additional diagnostic testing beyond MECP2 sequencing and http://jim.bmj.com/ background was otherwise normal without slowing in the majority chromosomal microarray should be considered for females of subjects. Commonly used antiseizure medications were val- with ASD, particularly with complex phenotypes. proate, levetiracetam, lamotrigine, and clobazam. 7/17 subjects achieved complete seizure control on a variety of medications. Conclusions We highlight a significant risk of epilepsy in NGLY1 deficiency and detail the clinical and electrographic 3 PHENOTYPIC CHARACTERIZATION OF WAC RELATED features identified in our international cohort. Seizure semiol- on October 2, 2021 by guest. Protected copyright. INTELLECTUAL DISABILITY DUE TO A NOVEL SPLICING ogy is varied, with predominant myoclonic, astatic and VARIANT absence seizure types with onset most commonly in infancy or early childhood. EEG abnormalities are non-specific and indi- 1JA Morales*, 2MI Valenzuela, 3BIsidor,2I Cusco-Marti, 1DR Matalon, 1N Gomez-Ospina. cate a genetic risk of epilepsy, but most patients do not have 1Stanford University, Stanford, CA; 2Hospital Universitari Vall d’Hebron, Barcelona, Spain; 3 EEG slowing which is a correlate of encephalopathy. Seizures CHU de Nantes – Hôtel Dieu, Nantes, France often require treatment with multiple medications. Commonly 10.1136/jim-2021-WRMC.3 used medications in various combinations include valproate and clobazam, indicating hepatic tolerance of these medica- Purpose of Study Describe the phenotype/natural history of 3 tions. Providers should educate caregivers about varied seizure non-related individuals with a novel splicing variant in the types to ensure prompt detection and treatment of epilepsy. WAC gene (c.381+4_381+7delAGTA). Provide proof of path- ogenicity to support variant reclassification as pathogenic. Methods Used Literature & retrospective chart review, clinical 2 CLINICAL WHOLE GENOME SEQUENCING IN YOUNG evaluation, in-silico & in-vitro RNA splicing studies. CHILDREN WITH AUTISM SPECTRUM DISORDER: A Summary of Results We identified 3 non-related boys from PILOT STUDY Mexican (P1), Spaniard (P2) and French (P3) ancestry carrying the same de novo splicing variant (c.381+4_381+7delAGTA) 1K Wigby*, 2TCarr,2M Feddock, 1A Jindal, 2D Dimmock, 2S Kingsmore, 1JFriedman, 2C Hobbs. 1University of California, San Diego, San Diego, CA; 2Rady Children’s Hospital in the WAC gene. All patients manifested with global develop- San Diego, San Diego, CA mental delay and intellectual disability (borderline - moderate). Except for non-specific mild dysmorphism, patients are healthy 10.1136/jim-2021-WRMC.2 without major medical comorbidities. J Investig Med 2021;69:102–296 103 Abstracts J Investig Med: first published as 10.1136/jim-2021-WRMC on 21 December 2020. Downloaded from All patients were ascertained through whole-exome sequenc- Conclusions Through bioinformatic analyses, we identified ing. For P1, variant was initially classified as of uncertain sig- CEP68 as a novel genetic determinant of insulin clearance and nificance (ClinVar). In-silico analysis showed location in the 5’ T2D. Our results suggest a model, where genetic variation at splice site of intron 4 and predicted loss of a splice site in rs2252867 affects CEP68 expression through altered chroma- exon 4. RNA experiments derived from P2 confirmed aber- tin-binding and transcription factor activity of PRDM10. rant splicing and showed a truncated protein: p.Gly92Alafs*2. Endosomal trafficking, a process mediated by microtubules, Review of literature & patient databases supported that which are organized in centrosomes, is integral to insulin WAC related intellectual disability is a condition characterized clearance. Based on our results, we hypothesize that, as a cen- by neurodevelopmental features of variable severity. Additional trosomal protein, CEP68 may have a role in the endosomal findings might include dysmorphism & seizures. Compared to process of insulin clearance and T2D susceptibility. The role patients with other variants, only 1 of our cohort shared the of CEP68 and PRDM10 in IC and T2D will be tested in described facial gestalt. Another overlapping condition, future functional studies. 10p11.2-p12.1 deletion, encompassing WAC and other genes, manifests with neurodevelopmental disorders and facial dys- morphism, suggesting that dysmorphism might be related to other gene/factor interactions. 5 URINE LUCK: A RARE CASE OF A CONGENITAL Conclusions In our small cohort with WAC intron 4 splicing DISORDER OF GLYCOSYLATION DIAGNOSED BY URINE variant, the common feature was developmental delay and OLIGOSACCHARIDES intellectual disability of variable severity. These data suggest weak genotype-phenotype correlations and support the contri- R Gates*, K Cusmano-Ozog, N Gomez-Ospina. Stanford University, Stanford, CA bution of other factors to the cognitive and dysmorphic phe- 10.1136/jim-2021-WRMC.5 notype. Based on the guidelines for interpretation of sequence variants, by performing functional studies and identifying non- Purpose of Study Congenital Disorders of Glycosylation (CDG) related individuals we provide sufficient evidence to classify are a group of disorders caused by defective synthesis and this variant as pathogenic. processing of glycoconjugates. Diagnosing CDGs can be diffi- cult due to their varied clinical presentations and multi-system organ involvement. Mannosyl-oligosaccharide glucosidase CDG (MOGS-CDG aka type IIb) is a very rare CDG with fewer 4 IDENTIFICATION OF CEP68 AS A CANDIDATE GENE FOR than ten reported cases in the literature. In addition to being INSULIN CLEARANCE AND TYPE 2 DIABETES poorly characterized, carbohydrate-deficient transferrin is typi- cally normal, hindering the diagnosis. Here, we report a case JH Nguyen*, M Peterfy. Western University of Health Sciences, Pomona, CA of MOGS-CDG, summarize the medical literature, and 10.1136/jim-2021-WRMC.4