Paediatrics (RCH) - Research Publications

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    Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
    Moller, P ; Seppala, T ; Dowty, JG ; Haupt, S ; Dominguez-Valentin, M ; Sunde, L ; Bernstein, I ; Engel, C ; Aretz, S ; Nielsen, M ; Capella, G ; Evans, DG ; Burn, J ; Holinski-Feder, E ; Bertario, L ; Bonanni, B ; Lindblom, A ; Levi, Z ; Macrae, F ; Winship, I ; Plazzer, J-P ; Sijmons, R ; Laghi, L ; Della Valle, A ; Heinimann, K ; Half, E ; Lopez-Koestner, F ; Alvarez-Valenzuela, K ; Scott, RJ ; Katz, L ; Laish, I ; Vainer, E ; Vaccaro, CA ; Carraro, DM ; Gluck, N ; Abu-Freha, N ; Stakelum, A ; Kennelly, R ; Winter, D ; Rossi, BM ; Greenblatt, M ; Bohorquez, M ; Sheth, H ; Tibiletti, MG ; Lino-Silva, LS ; Horisberger, K ; Portenkirchner, C ; Nascimento, I ; Rossi, NT ; da Silva, LA ; Thomas, H ; Zarand, A ; Mecklin, J-P ; Pylvanainen, K ; Renkonen-Sinisalo, L ; Lepisto, A ; Peltomaki, P ; Therkildsen, C ; Lindberg, LJ ; Thorlacius-Ussing, O ; von Knebel Doeberitz, M ; Loeffler, M ; Rahner, N ; Steinke-Lange, V ; Schmiegel, W ; Vangala, D ; Perne, C ; Hueneburg, R ; de Vargas, AF ; Latchford, A ; Gerdes, A-M ; Backman, A-S ; Guillen-Ponce, C ; Snyder, C ; Lautrup, CK ; Amor, D ; Palmero, E ; Stoffel, E ; Duijkers, F ; Hall, MJ ; Hampel, H ; Williams, H ; Okkels, H ; Lubinski, J ; Reece, J ; Ngeow, J ; Guillem, JG ; Arnold, J ; Wadt, K ; Monahan, K ; Senter, L ; Rasmussen, LJ ; van Hest, LP ; Ricciardiello, L ; Kohonen-Corish, MRJ ; Ligtenberg, MJL ; Southey, M ; Aronson, M ; Zahary, MN ; Samadder, NJ ; Poplawski, N ; Hoogerbrugge, N ; Morrison, PJ ; James, P ; Lee, G ; Chen-Shtoyerman, R ; Ankathil, R ; Pai, R ; Ward, R ; Parry, S ; Debniak, T ; John, T ; van Overeem Hansen, T ; Caldes, T ; Yamaguchi, T ; Barca-Tierno, V ; Garre, P ; Cavestro, GM ; Weitz, J ; Redler, S ; Buettner, R ; Heuveline, V ; Hopper, JL ; Win, AK ; Lindor, N ; Gallinger, S ; Le Marchand, L ; Newcomb, PA ; Figueiredo, J ; Buchanan, DD ; Thibodeau, SN ; ten Broeke, SW ; Hovig, E ; Nakken, S ; Pineda, M ; Duenas, N ; Brunet, J ; Green, K ; Lalloo, F ; Newton, K ; Crosbie, EJ ; Mints, M ; Tjandra, D ; Neffa, F ; Esperon, P ; Kariv, R ; Rosner, G ; Pavicic, WH ; Kalfayan, P ; Torrezan, GT ; Bassaneze, T ; Martin, C ; Moslein, G ; Ahadova, A ; Kloor, M ; Sampson, JR ; Jenkins, MA (BMC, 2022-10-01)
    OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
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    Polygenic risk score for embryo selection-not ready for prime time
    Polyakov, A ; Amor, DJ ; Savulescu, J ; Gyngell, C ; Georgiou, EX ; Ross, V ; Mizrachi, Y ; Rozen, G (OXFORD UNIV PRESS, 2022-07-19)
    Numerous chronic diseases have a substantial hereditary component. Recent advances in human genetics have allowed the extent of this to be quantified via genome-wide association studies, producing polygenic risk scores (PRS), which can then be applied to individuals to estimate their risk of developing a disease in question. This technology has recently been applied to embryo selection in the setting of IVF and preimplantation genetic testing, with limited data to support its utility. Furthermore, there are concerns that the inherent limitations of PRS makes it ill-suited for use as a screening test in this setting. There are also serious ethical and moral questions associated with this technology that are yet to be addressed. We conclude that further research and ethical reflection are required before embryo selection based on PRS is offered to patients outside of the research setting.
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    Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development
    Kaspi, A ; Hildebrand, MS ; Jackson, VE ; Braden, R ; van Reyk, O ; Howell, T ; Debono, S ; Lauretta, M ; Morison, L ; Coleman, MJ ; Webster, R ; Coman, D ; Goel, H ; Wallis, M ; Dabscheck, G ; Downie, L ; Baker, EK ; Parry-Fielder, B ; Ballard, K ; Harrold, E ; Ziegenfusz, S ; Bennett, MF ; Robertson, E ; Wang, L ; Boys, A ; Fisher, SE ; Amor, DJ ; Scheffer, IE ; Bahlo, M ; Morgan, AT (SPRINGERNATURE, 2022-09-18)
    Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.
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    Self-reported impact of developmental stuttering across the lifespan
    Boyce, JO ; Jackson, VE ; van Reyk, O ; Parker, R ; Vogel, AP ; Eising, E ; Horton, SE ; Gillespie, NA ; Scheffer, IE ; Amor, DJ ; Hildebrand, MS ; Fisher, SE ; Martin, NG ; Reilly, S ; Bahlo, M ; Morgan, AT (WILEY, 2022-03-21)
    AIM: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. METHOD: Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. RESULTS: A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). INTERPRETATION: The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. WHAT THIS PAPER ADDS: Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.
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    Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
    Stephenson, SEM ; Costain, G ; Blok, LER ; Silk, MA ; Nguyen, TB ; Dong, X ; Alhuzaimi, DE ; Dowling, JJ ; Walker, S ; Amburgey, K ; Hayeems, RZ ; Rodan, LH ; Schwartz, MA ; Picker, J ; Lynch, SA ; Gupta, A ; Rasmussen, KJ ; Schimmenti, LA ; Klee, EW ; Niu, Z ; Agre, KE ; Chilton, I ; Chung, WK ; Revah-Politi, A ; Au, PYB ; Griffith, C ; Racobaldo, M ; Raas-Rothschild, A ; Ben Zeev, B ; Barel, O ; Moutton, S ; Morice-Picard, F ; Carmignac, V ; Cornaton, J ; Marle, N ; Devinsky, O ; Stimach, C ; Wechsler, SB ; Hainline, BE ; Sapp, K ; Willems, M ; Bruel, A ; Dias, K-R ; Evans, C-A ; Roscioli, T ; Sachdev, R ; Temple, SEL ; Zhu, Y ; Baker, JJ ; Scheffer, IE ; Gardiner, FJ ; Schneider, AL ; Muir, AM ; Mefford, HC ; Crunk, A ; Heise, EM ; Millan, F ; Monaghan, KG ; Person, R ; Rhodes, L ; Richards, S ; Wentzensen, IM ; Cogne, B ; Isidor, B ; Nizon, M ; Vincent, M ; Besnard, T ; Piton, A ; Marcelis, C ; Kato, K ; Koyama, N ; Ogi, T ; Goh, ES-Y ; Richmond, C ; Amor, DJ ; Boyce, JO ; Morgan, AT ; Hildebrand, MS ; Kaspi, A ; Bahlo, M ; Fridriksdottir, R ; Katrinardottir, H ; Sulem, P ; Stefansson, K ; Bjornsson, HT ; Mandelstam, S ; Morleo, M ; Mariani, M ; Scala, M ; Accogli, A ; Torella, A ; Capra, V ; Wallis, M ; Jansen, S ; Waisfisz, Q ; de Haan, H ; Sadedin, S ; Lim, SC ; White, SM ; Ascher, DB ; Schenck, A ; Lockhart, PJ ; Christodoulou, J ; Tan, TY (CELL PRESS, 2022-04-07)
    Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
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    Family-centred care for children with traumatic brain injury and/or spinal cord injury: a qualitative study of service provider perspectives during the COVID-19 pandemic
    Pollock, A ; D'Cruz, K ; Scheinberg, A ; Botchway, E ; Harms, L ; Amor, DJ ; Anderson, V ; Bonyhady, B ; Knight, S (BMJ PUBLISHING GROUP, 2022-06-01)
    OBJECTIVES: COVID-19 has led to rapid changes in rehabilitation service provision for young people living with traumatic brain and/or spinal cord injury. The aim of this project was to understand the experiences of rehabilitation service providers during the acute response stage of the COVID-19 pandemic. Specifically, we aimed to identify innovative approaches to meeting the ongoing needs of young people with traumatic brain and/or spinal cord injury during this time. SETTING: This study was conducted at a research institute and involved remote interviews with key informants around Australia and internationally. PARTICIPANTS: Key informants from 11 services supporting children and/or adolescents with traumatic brain injury and/or spinal cord injury were interviewed using a semistructured interview guide. Interviews were transcribed and analysed using inductive thematic analysis. RESULTS: Three key themes emerged: (1) recognising and responding to the experiences of families during the pandemic, (2) the impact of greater use of telehealth on care delivery, and (3) realising opportunities to enhance family-centred care. CONCLUSIONS: These themes capture shifting perspectives and process changes relevant to longer term practice. Research findings suggest opportunities for future service development, enabling service delivery that is more family centred, flexible and efficient in meeting the needs of families. Understanding these experiences and the changed nature of service delivery provides important insights with implications for future service improvement.
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    Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities
    Chowdhury, F ; Wang, L ; Al-Raqad, M ; Amor, DJ ; Baxova, A ; Bendova, S ; Biamino, E ; Brusco, A ; Caluseriu, O ; Cox, NJ ; Froukh, T ; Gunay-Aygun, M ; Hancarova, M ; Haynes, D ; Heide, S ; Hoganson, G ; Kaname, T ; Keren, B ; Kosaki, K ; Kubota, K ; Lemons, JM ; Magrina, MA ; Mark, PR ; McDonald, MT ; Montgomery, S ; Morley, GM ; Ohnishi, H ; Okamoto, N ; Rodriguez-Buritica, D ; Rump, P ; Sedlacek, Z ; Schatz, K ; Streff, H ; Uehara, T ; Walia, JS ; Wheeler, PG ; Wiesener, A ; Zweier, C ; Kawakami, K ; Wentzensen, IM ; Lalani, SR ; Siu, VM ; Bi, W ; Balci, TB (SPRINGERNATURE, 2021-04-06)
    PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
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    A framework for reporting secondary and incidental findings in prenatal sequencing: When and for whom?
    Vears, D ; Amor, DJ (WILEY, 2022-01-19)
    As the use of genomic sequencing (GS) in the prenatal setting becomes more widespread, laboratories and clinicians will be tasked with making decisions about whether to offer incidental and secondary findings to expectant parents and, if so, which ones. Unfortunately, few guidelines or position statements issued by professional bodies address the return of secondary findings specifically in the context of prenatal GS, nor do they offer clear guidance on whether, and which types of incidental findings should be reported. Laboratories and clinicians will also need to navigate other challenges, such as how to obtain sufficiently informed consent, workload burdens for both laboratories and clinicians, and funding. Here we discuss these, and other challenges associated with offering incidental and secondary findings in the context of prenatal GS. We outline existing guidelines for return of these findings, prenatally and in children. We review the existing literature on stakeholder perspectives on return of incidental and secondary findings and discuss the main practical and ethical challenges that require consideration. We then propose a framework to help guide decision-making, suggesting a baseline routine analysis, with additional layers of analysis that could be offered, according to local laboratory policy, with additional opt-in consent from the parents.
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    Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow
    Godler, DE ; Ling, L ; Gamage, D ; Baker, EK ; Bui, M ; Field, MJ ; Rogers, C ; Butler, MG ; Murgia, A ; Leonardi, E ; Polli, R ; Schwartz, CE ; Skinner, CD ; Alliende, AM ; Santa Maria, L ; Pitt, J ; Greaves, R ; Francis, D ; Oertel, R ; Wang, M ; Simons, C ; Amor, DJ (AMER MEDICAL ASSOC, 2022-01-04)
    IMPORTANCE: Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment. OBJECTIVE: To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at population scale. DESIGN, SETTING, AND PARTICIPANTS: In this diagnostic study, the validation data set for the first-tier SNRPN test, called methylation-specific quantitative melt analysis (MS-QMA), included 109 PWS, 48 AS, 9 Dup15q, and 1190 population control newborn blood spots (NBS) and peripheral tissue samples from participants recruited from January 2000 to December 2016. The test data set included NBS samples from 16 579 infants born in 2011. Infants with an NBS identified as positive for PWS, AS, or Dup15q by the first-tier test were referred for droplet digital polymerase chain reaction, real-time polymerase chain reaction, and low-coverage whole-genome sequencing for confirmatory testing. Data analyses were conducted between February 12, 2015, and August 15, 2020. RESULTS: In the validation data set, the median age for the 77 patients with PWS was 3.00 years (IQR, 0.01-44.50 years); for the 46 patients with AS, 2.76 years (IQR, 0.028 to 49.00 years); and for the 9 patients with Dup15q, 4.00 years (IQR, 1.00 to 28.00 years). Thirty-eight patients (51.4%) in the PWS group, 20 patients (45.5%) in the AS group, and 6 patients (66.7%) in the Dup15q group who had sex reported were male. The validation data set showed MS-QMA sensitivity of 99.0% for PWS, 93.8% for AS, and 77.8% for Dup15q; specificity of 100% for PWS, AS, and Dup15q; positive predictive and negative predictive values of 100% for PWS and AS; and a positive predictive value of 87.5% and negative predictive value of 100% for Dup15q. In the test data set of NBS samples from 16 579 infants, 92 had a positive test result using a methylation ratio cut-off of 3 standard deviations from the mean. Of these patients, 2 were confirmed to have PWS; 2, AS; and 1, maternal Dup15q. With the use of more conservative PWS- and AS-specific thresholds for positive calls from the validation data set, 9 positive NBS results were identified by MS-QMA in this cohort. The 2 PWS and 2 AS calls were confirmed by second-tier testing, but the 1 Dup15q case was not confirmed. Together, these results provided prevalence estimates of 1 in 8290 for both AS and PWS and 1 in 16 579 for maternal Dup15q, with positive predictive values for first-tier testing at 67.0% for AS, 33.0% for PWS, and 44.0% for combined detection of chromosome 15 imprinting disorders for the validation data set. CONCLUSIONS AND RELEVANCE: The findings of this diagnostic study suggest that it is feasible to screen for all chromosome 15 imprinting disorders using SNRPN methylation analysis, with 5 individuals identified with these disorders out of 16 579 infants screened.
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    Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders
    Levy, MA ; McConkey, H ; Kerkhof, J ; Barat-Houari, M ; Bargiacchi, S ; Biamino, E ; Cappuccio, G ; Ciolfi, A ; Clarke, A ; DuPont, BR ; Elting, MW ; Faivre, L ; Fee, T ; Fletcher, RS ; Cherik, F ; Foroutan, A ; Friez, MJ ; Gervasini, C ; Haghshenas, S ; Hilton, BA ; Jenkins, Z ; Kaur, S ; Lewis, S ; Louie, RJ ; Maitz, S ; Milani, D ; Morgan, AT ; Oegema, R ; Ostergaard, E ; Pallares, NR ; Piccione, M ; Pizzi, S ; Plomp, AS ; Poulton, C ; Reilly, J ; Relator, R ; Rius, R ; Robertson, S ; Rooney, K ; Rousseau, J ; Santen, GWE ; Santos-Simarro, F ; Schijns, J ; Squeo, GM ; St John, M ; Thauvin-Robinet, C ; Traficante, G ; van der Sluijs, PJ ; Vergano, SA ; Vos, N ; Walden, KK ; Azmanov, D ; Balci, T ; Banka, S ; Gecz, J ; Henneman, P ; Lee, JA ; Mannens, MMAM ; Roscioli, T ; Siu, V ; Amor, DJ ; Baynam, G ; Bend, EG ; Boycott, K ; Brunetti-Pierri, N ; Campeau, PM ; Christodoulou, J ; Dyment, D ; Esber, N ; Fahrner, JA ; Fleming, MD ; Genevieve, D ; Kerrnohan, KD ; McNeill, A ; Menke, LA ; Merla, G ; Prontera, P ; Rockman-Greenberg, C ; Schwartz, C ; Skinner, SA ; Stevenson, RE ; Vitobello, A ; Tartaglia, M ; Alders, M ; Tedder, ML ; Sadikovic, B (ELSEVIER, 2022-01-13)
    Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.