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Deep Phenotyping in 3Q29 Deletion Syndrome: Recommendations for Clinical Care

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Deep Phenotyping in 3Q29 Deletion Syndrome: Recommendations for Clinical Care www.nature.com/gim ARTICLE Deep phenotyping in 3q29 deletion syndrome: recommendations for clinical care Rossana Sanchez Russo1,11, Michael J. Gambello1,11, Melissa M. Murphy1,11, Katrina Aberizk5, Emily Black1, T. Lindsey Burrell2,3, Grace Carlock1, Joseph F. Cubells1,4, Michael T. Epstein4, Roberto Espana5, Katrina Goines5, Ryan M. Guest5, Cheryl Klaiman2,3, Sookyong Koh2, Elizabeth J. Leslie1, Longchuan Li2,3, Derek M. Novacek6,7, Celine A. Saulnier2,8, Esra Sefik1,5, Sarah Shultz2,3, ✉ Elaine Walker5, Stormi Pulver White2,3, The Emory 3q29 Project* and Jennifer Gladys Mulle 1,9 PURPOSE: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. METHODS: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. RESULTS: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and fi – 1234567890():,; attention de cit hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. CONCLUSION: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients. Genetics in Medicine (2021) 23:872–880; https://doi.org/10.1038/s41436-020-01053-1 INTRODUCTION These data have revealed new aspects of 3q29 deletion syndrome Individuals with 3q29 deletion syndrome (OMIM 609425) are and provide guidance for the management of patients. hemizygous for a 1.6-Mb interval containing 21 protein coding genes.1 The syndrome (prevalence ~1 in 30,000) is associated with reduced birth weight, failure to thrive, heart defects, intellectual MATERIALS AND METHODS disability, anxiety disorder, autism spectrum disorder, and schizo- phrenia.1–6 Case reports have provided a rich source of data on Study subject eligibility 7 fl individual patients (reviewed in2). However, phenotyping in case The study design has been previously described. Brie y, individuals were recruited from the 3q29 registry3 (3q29deletion.org). Inclusion criteria were reports is not systematic, and can lead to bias in the curation of validated clinical diagnosis of 3q29 deletion syndrome where the subject’s 2 fi associated symptoms. Large cohorts of de-identi ed individuals deletion overlapped the canonical region (hg19, chr3:195725000–197350000) 5 ascertained for a specific phenotype (such as schizophrenia ) by ≥80%, and willingness and ability to travel to Atlanta, Georgia. Exclusion provide evidence of increased risk for a single manifestation, but criteria were any 3q29 deletion with less than 80% overlap with the canonical do not inform about the broader phenotypic spectrum. Systematic region, nonfluency in English, and age youngerthansixyears.Oneexception to the age criterion was made: a 4.85-year-old who was part of a previously self-report of phenotypes from registries are emerging but are 8 hampered by limitations of self-reported data.3,4 For these reasons described multiplex family was included in the current study. a comprehensive, unbiased characterization of the syndrome is 7 needed. Ethics statement The present study addresses these knowledge gaps; our clinical After informed consent, travel was arranged. Informed consent was team has directly and systematically evaluated 32 study subjects received from all participating study subjects. An informed consent session with the canonical 1.6-Mb 3q29 deletion using a standardized was conducted prior to the study visit, and repeated in-person at the phenotyping protocol that includes gold-standard instruments.7 beginning of the study visit. 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. 2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. 3Marcus Autism Center, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA. 4Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA. 5Department of Psychology, Emory University, Atlanta, GA, USA. 6Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA. 7Desert Pacific Mental Illness, Research, Education, and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. 8Neurodevelopmental Assessment & Consulting Services, Atlanta, GA, USA. 9Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. 11These authors contributed equally: Rossana Sanchez Russo, Michael J. Gambello, Melissa M. Murphy. *A list of authors and their affiliations appears at the end of the paper. ✉ email: [email protected] © The Author(s) 2021 R. Sanchez Russo et al. 873 Males Females older (n = 21); at younger ages, developmentally appropriate magical 3 thinking cannot be distinguished from true psychosis. All instruments were administered by trained personnel. A qualitative assessment of global 2 mental status was conducted by team psychiatrists (J.F.C., M.T.E.) to 1 supplement results from formal assessments. 0 Neuroimaging. Magnetic resonance imaging (MRI) data were collected = –1 from a subset of study subjects (n 24) on a Siemens Magnetom Prisma 3T scanner at the Center for Systems Imaging Core using a 32-channel –2 head coil. T1-weighted and T2-weighted high-resolution structural images were acquired. Specific details of the image acquisition parameters are provided in supplemental methods. Of the eight subjects who did not complete the MRI, two were at too low a developmental level to 2 successfully complete the procedure, one declined to participate, and five were medically ineligible. 1 = 0 Neurological exam. A subset of study subjects (n 23) were evaluated by a pediatric neurologist (S.K.) for gross and fine motor phenotypes, –1 including assessment of gait, heel to toe and stressed gait, fine finger movements, rapid alternating movements, as well as finger to nose and –2 heel to shin tests. Performance on each task was rated using a 4-point scale of impairment severity: 0 (none/normal), 1 (mild), 2 (moderate), and 3 (severe). Of the study subjects who did not have a neurology exam, nine joined the study before neurology assessment was added to the protocol. 2 For four study subjects, the neurologist was unavailable during the study visit. 1 0 –1 RESULTS FOC z-score z-score Weight Height z-score 1234567890():,; Participants –2 Thirty-two participants were consented and evaluated, including –3 four participants from a single family.8 Study subjects ranged in 510 20 30 510 20 30 age from 4.8 to 39.1 years (mean age 14.5 years, median age 11.7 Age (years) years); 62.5% (n = 20) were male (Table 1). Fig. 1 Z-scores for height, weight, and frontal occipital circum- ference (FOC) as a function of age, for males (blue, left panels) Medical history results and females (red, right panels). These data indicate the 3q29 deletion has an impact toward diminished height, weight, and FOC, A summary of characteristics reported in at least 10% of study and this is more pronounced at younger ages. subjects is presented in Table 1. Supplemental Table S2 includes characteristics reported in at least one study subject. The medical history review did not reveal prenatal/perinatal findings that were Evaluations generalizable across subjects. All study subjects were evaluated over two days. Subjects were directed to take medications as they normally would. Evaluations were conducted as described in the following sections (summarized in Table S1). Ear, nose, and throat (ENT) Seventy-eight percent of study subjects (n = 25) had an ENT- Medical history and physical examination. Parents completed a compre- related symptom or diagnosis in their medical history. Twenty-two hensive medical history (Supplementary Materials), reviewed during the percent (n = 7) had recurrent ear infections, and three subjects visit with a medical geneticist (E.B., R.S.R., M.J.G.), who also completed a required surgery. Fifty-nine percent (n = 19) had a symptom or physical examination of the study subject. Following study visits, the diagnosis related to the eye. The most common ocular phenotype medical geneticists met to identify relevant characteristics by system and = classify characteristcs using Human Phenotype Ontology (HPO) terminol- was strabismus (28%, n 9), with three subjects requiring surgery. ogy (https://hpo.jax.org/app/). Assessment of craniofacial features is Vision problems encountered later in childhood included astig- reported elsewhere.9 Z-scores and percentiles
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