A decade of whole-exome sequencing in Brazilian Neurology: from past insights to future perspectives

Caio Robledo D'Angioli Costa Quaio; Thiago Yoshinaga Tonholo Silva; Orlando G. Barsottini; Sarah Teixeira Camargos; Marcondes C. França Junior; Jonas A. Saute; Wilson Marques Junior; Fernando Kok; José Luiz Pedroso

doi:10.1055/s-0045-1807715

Arquivos de Neuro-Psiquiatria, Table of Contents

CC BY 4.0 · Arq Neuropsiquiatr 2025; 83(04): s00451807715
DOI: 10.1055/s-0045-1807715

Review Article

A decade of whole-exome sequencing in Brazilian Neurology: from past insights to future perspectives

Caio Robledo D'Angioli Costa Quaio

¹Hospital Israelita Albert Einstein, São Paulo SP, Brazil.

²Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto da Criança, São Paulo SP, Brazil.

,

Thiago Yoshinaga Tonholo Silva

¹Hospital Israelita Albert Einstein, São Paulo SP, Brazil.

³Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.

,

Orlando G. Barsottini

¹Hospital Israelita Albert Einstein, São Paulo SP, Brazil.

³Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.

,

Sarah Teixeira Camargos

⁴Universidade Federal de Minas Gerais, Belo Horizonte MG, Brazil.

,

Marcondes C. França Junior

⁵Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.

,

Jonas A. Saute

⁶Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil.

⁷Hospital de Clínicas de Porto Alegre, Serviço de Genética Médica, Porto Alegre RS, Brazil.

,

Wilson Marques Junior

⁸Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Neurociências e Ciências do Comportamento, Ribeirão Preto SP, Brazil.

,

Fernando Kok

⁹Mendelics Análise Genômica, São Paulo SP, Brazil.

¹⁰Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.

,

José Luiz Pedroso

¹Hospital Israelita Albert Einstein, São Paulo SP, Brazil.

³Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.

› Author Affiliations

Abstract

Over the last decade, whole-exome sequencing (WES) has become a standard diagnostic tool, significantly transforming the landscape of clinical genetics and playing a pivotal role in the diagnosis of neurogenetic diseases. This revolutionary shift has left a lasting impact on the field of neurology in Brazil. The current review article examines key developments and milestones achieved in Brazil through the application of WES in neurology and discusses forthcoming challenges and essential steps to advance molecular diagnosis. Several studies report the use of WES to diagnose genetic disorders with neurological manifestations in Brazil, underscoring the growing importance of molecular diagnosis in neurogenetics. These studies often provide detailed phenotypic analyses and clinical descriptions, offering valuable insights into the genetic underpinnings of several neurological conditions. Many reports highlight the use of WES in the investigation of complex neurological conditions in Brazil, such as neurodevelopmental disorders, hereditary spastic paraplegia, movement disorders, and ataxia. The discovery of new genes implicated in monogenic diseases with neurological manifestations through WES was a significant breakthrough. Despite these advances, the availability of large cohort studies on rare diseases in Brazil remains limited, hindering the ability to generalize findings and explore the full spectrum of genetic diversity. However, a few larger cohort studies have substantially contributed to our understanding of rare diseases and specific neurological disorders.

While WES has limitations and may eventually be supplanted by more advanced diagnostic tools, it left a permanent mark on the neurology field in Brazil. The field of neurogenetics is set to become increasingly important in the future.

Keywords

Exome Sequencing - Neurology - Molecular Diagnostic Techniques - Brazil

Bibliographical Record
Caio Robledo D'Angioli Costa Quaio, Thiago Yoshinaga Tonholo Silva, Orlando G. Barsottini, Sarah Teixeira Camargos, Marcondes C. França, Jonas A. Saute, Wilson Marques, Fernando Kok, José Luiz Pedroso. A decade of whole-exome sequencing in Brazilian Neurology: from past insights to future perspectives. Arq Neuropsiquiatr 2025; 83: s00451807715.
DOI: 10.1055/s-0045-1807715

Full Text

References

References
1 Sullivan JA, Schoch K, Spillmann RC, Shashi V. Exome/Genome Sequencing in Undiagnosed Syndromes. Annu Rev Med 2023; 74: 489-502
2 Wakap SN, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020; 28 (02) 165-173
3 Corominas J, Smeekens SP, Nelen MR, Yntema HG, Kamsteeg E-J, Pfundt R, Gilissen C. Clinical exome sequencing-Mistakes and caveats. Hum Mutat 2022; 43 (08) 1041-1055
4 Seaby EG, Pengelly RJ, Ennis S. Exome sequencing explained: a practical guide to its clinical application. Brief Funct Genomics 2016; 15 (05) 374-384
5 Nurk S, Koren S, Rhie A, Rautiainen M, Bzikadze AV, Mikheenko A. et al. The complete sequence of a human genome. Science 2022; 376 (6588) 44-53
6 Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE. et al. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry 2017; 22 (04) 615-624
7 Girirajan S, Campbell CD, Eichler EE. Human copy number variation and complex genetic disease. Annu Rev Genet 2011; 45: 203-226
8 Shendure J, Balasubramanian S, Church GM, Gilbert W, Rogers J, Schloss JA, Waterston RH. DNA sequencing at 40: past, present and future. Nature 2017; 550 (7676) 345-353 Erratum in: Nature. 2019 Apr;568(7752):E11. PMID: 29019985
9 Adams DR, Eng CM. Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. N Engl J Med 2018; 379 (14) 1353-1362
10 Silveira-Moriyama L, Paciorkowski AR. Genetic Diagnostics for Neurologists. Continuum (Minneap Minn) 2018; 24 (1, Child Neurology): 18-36 . PMID: 29432235
11 Lennon NJ, Kottyan LC, Kachulis C, Abul-Husn NS, Arias J, Belbin G. et al; GIANT Consortium, All of Us Research Program. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations. Nat Med 2024; 30 (02) 480-487
12 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
13 Rexach J, Lee H, Martinez-Agosto JA, Németh AH, Fogel BL. Clinical application of next-generation sequencing to the practice of neurology. Lancet Neurol 2019; 18 (05) 492-503
14 Hehir-Kwa JY, Tops BBJ, Kemmeren P. The clinical implementation of copy number detection in the age of next-generation sequencing. Expert Rev Mol Diagn 2018; 18 (10) 907-915
15 Dillon OJ, Lunke S, Stark Z, Yeung A, Thorne N. Gaff C. et al; Melbourne Genomics Health Alliance. Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders. Eur J Hum Genet 2018; 26 (05) 644-651
16 Quaio CRDC, Obando MJR, Perazzio SF, Dutra AP, Chung CH, Moreira CM. et al. Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases. Genet Mol Biol 2021; 44 (04) 20210061
17 Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, Kingsmore SF. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med 2018; 3: 16
18 Van der Sanden BPGH, Schobers G, Galbany JC, Koolen DA, Sinnema M, van Reeuwijk J. et al. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet 2023; 31 (01) 81-88
19 Chung CCY, Hue SPY, Ng NYT, Doong PHL, Chu ATW, Chung BHY. Hong Kong Genome Project. Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations. Genet Med 2023; 25 (09) 100896
20 Dimmock D, Caylor S, Waldman B, Benson W, Ashburner C, Carmichael JL. et al. Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care. Am J Hum Genet 2021; 108 (07) 1231-1238
21 Chung CCY, Chu ATW, Chung BHY. Hong Kong Genome Project. Rare disease emerging as a global public health priority. Front Public Health 2022; 10: 1028545
22 Brooks PJ, Urv TK, Parisi MA. Gene-targeted therapies: Overview and implications. Am J Med Genet C Semin Med Genet 2023; 193 (01) 13-18
23 Martinez-Martin N, Magnus D. Privacy and ethical challenges in next-generation sequencing. Expert Rev Precis Med Drug Dev 2019; 4 (02) 95-104
24 Garcia CAB, Carvalho SCS, Yang X, Ball LL, George RD, James KN. et al. mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly. Epilepsia Open 2020; 5 (01) 97-106
25 Abrahao A, Abath O, Neto, Kok F, Zanoteli E, Santos B, Pinto WBVR. et al. One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia. J Neurol Sci 2016; 368: 352-358
26 Prota J, Rizzi L, Bonadia L, Souza LCd, Caramelli P, Secolin R. et al. Slowly progressive behavioral frontotemporal dementia syndrome in a family co-segregating the C9orf72 expansion and a Synaptophysin mutation. Alzheimers Dement 2022; 18 (03) 523-528
27 Shinjo SK, Oba-Shinjo SM, Lerario AM, Marie SKN. A Brazilian family with inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia linked to the VCP pGly97Glu mutation. Clin Rheumatol 2018; 37 (04) 1129-1136
28 Soares IFZ, Christofolini DM, Silva LG, Feder D, Carvalho AAdS. Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia. Mol Genet Genomic Med 2020; 8 (11) e1491
29 Moreno CA, Metze K, Lomazi EA, Bertola DR, Barbosa RHA, Cosentino V. et al. Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. Am J Med Genet A 2016; 170 (11) 2965-2974
30 Silva AMS, Camelo CG, Matsui-Júnior C, Mendonça RdH, Campos LM, Elias AM. et al. Child Neurology: A Case of FHL1-Related Disease Presenting as Inflammatory Myopathy. Neurology 2021; 96 (09) e1383-e1386
31 Brito LA, Nóbrega PR, Dias DA, Barreto ARF, Freitas HC, Kok F, Rodrigues CL. New observations on minifascicular neuropathy with sex-dependent gonadal dysgenesis: a case series with nerve ultrasound assessment. Neurol Sci 2023; 44 (10) 3691-3696
32 Maciel VAZ, Maximiano-Alves G, Frezatti RSS, Alves ALDM, Andrade BMA, Leal RDCC. et al. Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families. J Peripher Nerv Syst 2023; 28 (04) 614-619
33 Pedroso JL, Rocha CR, Macedo-Souza LI, DeMario V, Marques Jr W, Barsottini OGP. et al. Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease. Neurol Genet 2015; 1 (04) e30
34 Pinto WBVR, Nunes PP, Teixeira ILE, Assis ACD, Naylor FGM, Chieia MAT. et al. O'Sullivan-McLeod syndrome: Unmasking a rare atypical motor neuron disease. Rev Neurol (Paris) 2019; 175 (1-2): 81-86
35 Freua F, Almeida MEC, Nóbrega PR, Paiva ARBd, Della-Ripa B, Cunha P. et al. Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia. Cold Spring Harb Mol Case Stud 2022; 8 (06) a006232 ; Epub ahead of print
36 Oliveira MGd, Tengan C, Micheletti C, Macedo PRd, Cernach MCSP, Cavole TR. et al. A novel variant in the COX15 gene causing a fatal infantile cardioencephalomyopathy: A case report with clinical and molecular review. Eur J Med Genet 2021; 64 (05) 104195
37 Linhares ND, Wilk P, Wątor E, Tostes MA, Weiss MS, Pena SDJ. Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase Deficiency diagnosed by exome sequencing. Genet Mol Biol 2021; 44 (02) e20200393
38 Souza PVS, Bortholin T, Teixeira CAC, Seneor DD, Marin VDGB, Dias RB. et al. Leigh syndrome caused by mitochondrial DNA-maintenance defects revealed by whole exome sequencing. Mitochondrion 2019; 49: 25-34
39 Barcelos IPd, Bueno C, Godoy LFS, Pessoa A, Costa LA, Monti FC. et al. Subacute Partially Reversible Leukoencephalopathy Expands the Aicardi-Goutières Syndrome Phenotype. Brain Sci 2023; 13 (08) 1169
40 Souza PVSd, Bortholin T, Burlin S, Naylor FGM, Pinto WBVR, Oliveira ASB. NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy. J Pediatr Genet 2018; 7 (01) 40-42
41 Ferreira LD, Oliveira JRMd. Overlapping Diseases in a Brazilian Subject with Brain Calcification Linked to Novel Phenotypes. J Mol Neurosci 2020; 70 (08) 1255-1256
42 Monteiro FP, Curry CJ, Hevner R, Elliott S, Fisher JH, Turocy J. et al. Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations. Eur J Med Genet 2020; 63 (01) 103624
43 Richieri-Costa A, Zechi-Ceide RM, Candido-Souza RM, Monteiro RAC, Tonello C, Freitas MLd. et al. Holoprosencephaly, orofacial cleft, and frontonaso-orbital encephaloceles: Genetic evaluation of a possible new syndrome. Am J Med Genet A 2019; 179 (11) 2170-2177
44 Vieira NM, Naslavsky MS, Licinio L, Kok F, Schlesinger D, Vainzof M. et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum Mol Genet 2014; 23 (15) 4103-4110
45 Melo US, Macedo-Souza LI, Figueiredo T, Muotri AR, Gleeson JG, Coux G. et al. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum Mol Genet 2015; 24 (24) 6877-6885
46 Rebelo AP, Tomaselli PJ, Medina J, Wang Y, Dohrn MF, Nyvltova E. et al. Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs. Brain 2023; 146 (10) 4191-4199
47 Figueiredo T, Melo US, Pessoa AL, Nobrega PR, Kitajima JP, Correa I. et al. Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family. J Med Genet 2015; 52 (02) 123-127
48 Figueiredo T, Melo US, Pessoa AL, Nobrega PR, Kitajima JP, Rusch H. et al. A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability. Mol Psychiatry 2016; 21 (08) 1125-1129
49 Garcia-Rosa S, Trivella DB, Marques VD, Serafim RB, Pereira JGc, Lorenzi CcJ. et al. A non-functional galanin receptor-2 in a multiple sclerosis patient. Pharmacogenomics J 2019; 19 (01) 72-82
50 Cappi C, Brentani H, Lima L, Sanders SJ, Zai G, Diniz BJ. et al. Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways. Transl Psychiatry 2016; 6 (03) e764
51 Lima LdA, Feio-dos-Santos AC, Belangero SI, Gadelha A, Bressan RA, Salum GA. et al. An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder. Sci Rep 2016; 6: 22851 Erratum in: Sci Rep. 2016 May 24;6:25861. PMID: 26947246; PMCID: PMC4780010
52 Cappi C, Oliphant ME, Péter Z, Zai G, Rosário MCd, Sullivan CAW. et al. De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism. Biol Psychiatry 2020; 87 (12) 1035-1044
53 Zanardo ÉA, Monteiro FP, Chehimi SN, Oliveira YG, Dias AT, Costa LA. et al. Application of Whole-Exome Sequencing in Detecting Copy Number Variants in Patients with Developmental Delay and/or Multiple Congenital Malformations. J Mol Diagn 2020; 22 (08) 1041-1049
54 Raposo M, Bettencourt C, Melo ARV, Ferreira AF, Alonso I, Silva P. et al. Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing. Neurobiol Dis 2022; 162: 105578
55 Souza LS, Almeida CF, Yamamoto GL, Pavanello RdCM, Gurgel-Giannetti J, Costa SSd. et al. Manifesting carriers of X-linked myotubular myopathy: Genetic modifiers modulating the phenotype. Neurol Genet 2020; 6 (05) e513
56 Quaio CRDC, Ceroni JRM, Cervato MC, Thurow HS, Moreira CM, Trindade ACG. et al. Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases. Sci Rep 2022; 12 (01) 7764
57 Souza PVS, Bortholin T, Dias RB, Chieia MAT, Burlin S, Naylor FGM. et al. New genetic causes for complex hereditary spastic paraplegia. J Neurol Sci 2017; 379: 283-292
58 Carneiro TN, Krepischi AC, Costa SS, Silva ITd, Vianna-Morgante AM, Valieris R. et al. Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases. Appl Clin Genet 2018; 11: 93-98
59 Homma TK, Freire BL, Kawahira RSH, Dauber A, Funari MFdA, Lerario AM. et al. Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing. J Pediatr 2019; 215: 192-198 Erratum in: J Pediatr. 2020 Mar;218:e3. PMID: 31630891
60 Montenegro EMSd, Costa CS, Campos G, Scliar M, Almeida TFd, Zachi RC. et al. Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort. Autism Res 2020; 13 (02) 199-206
61 Quaio CRDC, Moreira CM, Novo-Filho GM, Sacramento-Bobotis PR, Penna MG, Perazzio SF. et al. Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. Am J Med Genet C Semin Med Genet 2020; 184 (04) 955-964
62 Quaio CRDC, Moreira CM, Chung CH, Perazzio SF, Dutra AP, Kim CA. Exome sequencing of 500 Brazilian patients with rare diseases: what we have learned. Sao Paulo Med J 2022; 140 (05) 734-736
63 Giordani GM, Diniz F, Fussiger H, Gonzalez-Salazar C, Donis KC, Freua F. et al. Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias. Sci Rep 2021; 11 (01) 22248
64 Gonçalves JPN, Leoni TB, Martins MP, Peluzzo TM, Dourado Jr MET, Saute JAM. et al. Genetic epidemiology of familial ALS in Brazil. Neurobiol Aging 2021; 102: 227.e1-227.e4
65 Carvalho LML, D'Angelo CS, Villela D, Costa SSd, Jorge AAdL, Silva ITd. et al. Genetic investigation of syndromic forms of obesity. Int J Obes (Lond) 2022; 46 (09) 1582-1586
66 Graça FFd, Peluzzo TM, Bonadia LC, Martinez ARM, Lima FDd, Pedroso JL. et al. Diagnostic Yield of Whole Exome Sequencing for Adults with Ataxia: a Brazilian Perspective. Cerebellum 2022; 21 (01) 49-54
67 Leite AJDC, Pinto IP, Leijsten N, Ruiterkamp-Versteeg M, Pfundt R, Leeuw Nd. et al. Diagnostic yield of patients with undiagnosed intellectual disability, global developmental delay and multiples congenital anomalies using karyotype, microarray analysis, whole exome sequencing from Central Brazil. PLoS One 2022; 17 (04) e0266493
68 Atique Tacla M, Copelli MdM, Pairet E, Monlleó IL, Ribeiro EM, Mendes EL. et al. Molecular investigation in individuals with orofacial clefts and microphthalmia-anophthalmia-coloboma spectrum. Eur J Hum Genet 2024; 32 (10) 1257-1266
69 Chaves LD, Carvalho LML, Tolezano GC, Pires SF, Costa SS, Scliar MOd. et al. Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants. Mol Neurobiol 2023; 60 (07) 3758-3769
70 Fussiger H, Pereira BLDS, Padilha JPD, Donis KC. Siebert M, Brusius-Facchin AC. et al; Rare-Genomes Project Consortium. Copy number variations in SPAST and ATL1 are rare among Brazilians. Clin Genet 2023; 103 (05) 580-584
71 Novis LE, Alavi S, Pellerin D, Della Coleta MV, Raskin S, Spitz M. et al. Unraveling the genetic landscape of undiagnosed cerebellar ataxia in Brazilian patients. Parkinsonism Relat Disord 2024; 119: 105961
72 Figueiredo FB, Tomaselli PJ, Hallak J, Mattiello-Sverzut AC, Covaleski APPM, Sobreira CFdR. et al. Genetic diversity in hereditary axonal neuropathy: Analyzing 53 Brazilian children. J Peripher Nerv Syst 2024; 29 (01) 97-106
73 Silveira HG, Steiner CE, Toccoli G, Angeloni LL, Heleno JL, Spineli-Silva S. et al. Variants in KMT2A in Three Individuals with Previous Suspicion of 22q11.2 Deletion Syndrome. Genes (Basel) 2024; 15 (02) 211
74 Tolezano GC, Bastos GC, Costa SSd, Scliar MOd, Souza CFMd, Van Der Linden Jr H. et al. Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders. Mol Neurobiol 2024; 61 (08) 5230-5247 ; Epub ahead of print
75 Quaio CRDC, Ceroni JRM, Pereira MA, Teixeira ACB, Yamada RY, Cintra VP. et al. The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023. Hum Genomics 2023; 17 (01) 102
76 Félix TM, Souza CFMd, Oliveira JB, Rico-Restrepo M, Zanoteli E, Zatz M, Giugliani R. Challenges and recommendations to increasing the use of exome sequencing and whole genome sequencing for diagnosing rare diseases in Brazil: an expert perspective. Int J Equity Health 2023; 22 (01) 11
77 Conitec, Ministério da Saúde. Protocolo para Diagnóstico Etiológico da Deficiência Intelectual. Brasilia-DF, Brazil. 2020 . Available at: https://www.gov.br/conitec/pt-br/midias/relatorios/2020/20201203_relatorio_572_pcdt_deficiencia-intelectual_.pdf
78 Agência Nacional de Saúde Suplementar. ANEXO II, DIRETRIZES DE UTILIZAÇÃO PARA COBERTURA DE PROCEDIMENTOS NA SAÚDE SUPLEMENTAR (RN 465/2021 e suas alterações). Brazil. 2021 . Available at: https://www.gov.br/ans/pt-br/arquivos/assuntos/consumidor/o-que-seu-plano-deve-cobrir/Anexo_II_DUT_2021_RN_465.2021_tea.br_RN473_RN477_RN478_RN480_RN513_RN536.pdf
79 Souche E, Beltran S, Brosens E, Belmont JW, Fossum M, Riess O. et al. Recommendations for whole genome sequencing in diagnostics for rare diseases. Eur J Hum Genet 2022; 30 (09) 1017-1021
80 Ibañez K, Polke J, Hagelstrom RT, Dolzhenko E, Pasko D, Thomas ERA. et al; WGS for Neurological Diseases Group, Genomics England Research Consortium. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol 2022; 21 (03) 234-245
81 Schoch K, Esteves C, Bican A, Spillmann R, Cope H, McConkie-Rosell A. et al; Undiagnosed Diseases Network. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science. Genet Med 2021; 23 (02) 259-271
82 Deignan JL, Chung WK, Kearney HM, Monaghan KG, Rehder CW, Chao EC. ACMG Laboratory Quality Assurance Committee. Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2019; 21 (06) 1267-1270
83 Wu B, Kang W, Wang Y, Zhuang D, Chen L, Li L. et al. Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project. Crit Care Med 2021; 49 (10) 1674-1683
84 Van Dijk EL, Jaszczyszyn Y, Naquin D, Thermes C. The Third Revolution in Sequencing Technology. Trends Genet 2018; 34 (09) 666-681
85 Kernohan KD, Boycott KM. The expanding diagnostic toolbox for rare genetic diseases. Nat Rev Genet 2024; 25 (06) 401-415