New Deletion of Multiple Genes in the Pathogenic Subtelomeric Region is Related to the Phenotypic Heterogeneity of Patients with Polymalformation Syndrome
Journal: Advances in Medicine and Engineering Interdisciplinary Research DOI: 10.32629/ameir.v3i1.3656
Abstract
Introduction: Genomic testing has advanced significantly, enabling the identification of changes ranging from specific locus modifications to genomic structural alterations. This has improved the diagnosis of diseases and the understanding of little-known genetic disorders. Objective: To describe the case of an adolescent with no consanguineous parents and no family history of genetic variants but with cognitive-behavioral impairment, epilepsy, hypothyroidism, tall stature, and minor facial dysmorphisms suggestive of an overgrowth syndrome. Due to the complexity of the patient's phenotype affecting multiple organs and systems, the patient underwent aCGH analysis to identify deletions or duplications. Methods: Genomic DNA was extracted from a peripheral blood sample of the patient. The DNA was labeled and hybridized using the Agilent® SurePrint G3 Human CGH array 4x180K. The data were scanned and analyzed with the Agilent CytoGenomics v5® software. Results: The aCGH analysis identified a sub-telomeric pathogenic heterozygous deletion in the chromosomal region 5q35.2-q35.3. A search was conducted in the Online Mendelian Inheritance in Man, Clinical Genome Resource, and GeneScout databases, where 12 out of 74 genes were associated with medical conditions. Of these, 9 had autosomal recessive inheritance mechanisms and the remaining 3 had autosomal dominant (AD) inheritance. For genes with AD and unclear inheritance mechanisms, and with a high risk of genotype/phenotype correlation (reversed phenotype, crucial for precise diagnosis), a Human Phenotype Ontology search was conducted. This search related the deletion to conditions such as hematological malignancy predisposition syndrome, hereditary angioedema, infantile hypercalcemia 2, Fanconi renotubular syndrome 2, nephrolithiasis/hypophosphatemic osteoporosis 1, Lewy body dementia, and Sotos syndrome. This deletion is associated with a complex phenotype, including autism spectrum disorder and several physical anomalies. Conclusions: Genetic tests such as aCGH are fundamental for diagnosing congenital anomalies and neurodevelopmental disorders. Identifying deletions in the 5q35 region enhances the understanding of polymalformative syndromes and facilitates genetic counseling, thereby improving prognosis and family planning for patients.
Keywords
neurodevelopment; conduct; autism; epilepsy; genomics; precision medicine
Full Text
PDF - Viewed/Downloaded: 0 TimesReferences
[1] Lalonde E, Rentas S, Lin F, Dulik MC, Skraban CM, Spinner NB. Genomic Diagnosis for Pediatric Disorders: Revolution and Evolution. Front Pediatr. 8 de julio de 2020;8:498541.
[2] Xu C, Li M, Gu T, Xie F, Zhang Y, Wang D, et al. Chromosomal microarray analysis for prenatal diagnosis of uniparental disomy: a retrospective study. Mol Cytogenet [Internet]. 1 de diciembre de 2024 [citado 17 de febrero de 2024];17(1):1-7. Disponible en: https://molecularcytogenetics.biomedcentral.com/articles/10.1186/s13039-023-00668-8
[3] Qian G, Cai L, Yao H, Dong X. Chromosome microarray analysis combined with karyotype analysis is a powerful tool for the detection in pregnant women with high-risk indicators. BMC Pregnancy Childbirth [Internet]. 1 de diciembre de 2023 [citado 17 de febrero de 2024];23(1):1-7. Disponible en: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-023-06052-z
[4] Savatt JM, Myers SM. Genetic Testing in Neurodevelopmental Disorders. Front Pediatr. 19 de febrero de 2021;9:526779.
[5] Zhang L, Tie X, Che F, Wang G, Ge Y, Li B, et al. Novel maternal duplication of 6p22.3-p25.3 with subtelomeric 6p25.3 deletion: new clinical findings and genotype–phenotype correlations. Mol Cytogenet [Internet]. 1 de diciembre de 2023 [citado 28 de enero de 2024];16(1):11. Disponible en: /pmc/articles/PMC10259020/
[6] Wu D, Wu Y, Lan Y, Lan S, Zhong Z, Li D, et al. Chromosomal Aberrations in Pediatric Patients With Moderate/Severe Developmental Delay/Intellectual Disability With Abundant Phenotypic Heterogeneities: A Single-Center Study. Pediatr Neurol [Internet]. 1 de octubre de 2023 [citado 17 de febrero de 2024];147:72-81. Disponible en: http://www.pedneur.com/article/S088789942300173X/fulltext
[7] Lalonde E, Rentas S, Lin F, Dulik MC, Skraban CM, Spinner NB. Genomic Diagnosis for Pediatric Disorders: Revolution and Evolution. Front Pediatr. 8 de julio de 2020;8:498541.
[8] Qian G, Cai L, Yao H, Dong X. Chromosome microarray analysis combined with karyotype analysis is a powerful tool for the detection in pregnant women with high-risk indicators. BMC Pregnancy Childbirth [Internet]. 1 de diciembre de 2023 [citado 17 de febrero de 2024];23(1):1-7. Disponible en: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-023-06052-z
[9] Savatt JM, Myers SM. Genetic Testing in Neurodevelopmental Disorders. Front Pediatr. 19 de febrero de 2021;9:526779.
[10] Danecek P, Gardner EJ, Fitzgerald TW, Gallone G, Kaplanis J, Eberhardt RY, et al. Detection and characterisation of copy number variants from exome sequencing in the DDD study. Genetics in Medicine Open [Internet]. 28 de enero de 2024 [citado 27 de febrero de 2024];101818. Disponible en: https://linkinghub.elsevier.com/retrieve/pii/S2949774424009646
[11] Zhang L, Tie X, Che F, Wang G, Ge Y, Li B, et al. Novel maternal duplication of 6p22.3-p25.3 with subtelomeric 6p25.3 deletion: new clinical findings and genotype–phenotype correlations. Mol Cytogenet [Internet]. 1 de diciembre de 2023 [citado 28 de enero de 2024];16(1):11. Disponible en: /pmc/articles/PMC10259020/
[12] Human hg38 chr5:176,517,339-179,570,928 UCSC Genome Browser v459 [Internet]. [citado 27 de enero de 2024]. Disponible en: https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr5%3A176517339%2D179570928&hgsid=1896488230_BSeIQBO4uuZ3glaFUKsCS45JP7iN
[13] Search - GeneScout [Internet]. [citado 2 de mayo de 2024]. Disponible en: https://genescout.omim.org/search?primaryCoordinates=chr5%3A176517339-179570928&assembly=GRCh38&comparisonCoordinates=&operation=intersect#
[14] Ravel JM, Renaud M, Muller J, Becker A, Renard É, Remen T, et al. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study. Genome Med [Internet]. 1 de diciembre de 2023 [citado 21 de febrero de 2024];15(1):1-10. Disponible en: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-023-01191-6
[15] Sandoval-Talamantes AK, Mori MÁ, Santos-Simarro F, García-Miñaur S, Mansilla E, Tenorio JA, et al. Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital. Genes 2023, Vol 14, Page 820 [Internet]. 29 de marzo de 2023 [citado 17 de febrero de 2024];14(4):820. Disponible en: https://www.mdpi.com/2073-4425/14/4/820/htm
[16] Miceli M, Failla P, Saccuzzo L, Galesi O, Amata S, Romano C, et al. Trait - driven analysis of the 2p15p16.1 microdeletion syndrome suggests a complex pattern of interactions between candidate genes. Genes Genomics [Internet]. 1 de abril de 2023 [citado 18 de mayo de 2024];45(4):491-505. Disponible en: https://pubmed.ncbi.nlm.nih.gov/36807877/
[17] Tritto V, Eoli M, Paterra R, Redaelli S, Moscatelli M, Rusconi F, et al. Characterization of 22q12 Microdeletions Causing Position Effect in Rare NF2 Patients with Complex Phenotypes. Int J Mol Sci [Internet]. 1 de septiembre de 2022 [citado 18 de mayo de 2024];23(17). Disponible en: /pmc/articles/PMC9456353/
[18] Micale L, Morlino S, Carbone A, Carissimo A, Nardella G, Fusco C, et al. Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement. Genet Med [Internet]. 1 de febrero de 2022 [citado 18 de mayo de 2024];24(2):439-53. Disponible en: https://pubmed.ncbi.nlm.nih.gov/34906501/
[19] Jønch AE, Douard E, Moreau C, Van Dijck A, Passeggeri M, Kooy F, et al. Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice. J Med Genet [Internet]. 1 de octubre de 2019 [citado 18 de mayo de 2024];56(10):701-10. Disponible en: https://pubmed.ncbi.nlm.nih.gov/31451536/
[20] Nunes N, Carvalho Nunes B, Zamariolli M, Cordeiro de Queiroz Soares D, Caires Dos Santos L, Gollo Dantas A, et al. Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome. Genet Res (Camb) [Internet]. 2024 [citado 18 de mayo de 2024];2024:5549592. Disponible en: https://pubmed.ncbi.nlm.nih.gov/38586596/
[21] Zinkstok JR, Boot E, Bassett AS, Hiroi N, Butcher NJ, Vingerhoets C, et al. Neurobiological perspective of 22q11.2 deletion syndrome. Lancet Psychiatry [Internet]. 1 de noviembre de 2019 [citado 18 de mayo de 2024];6(11):951. Disponible en: /pmc/articles/PMC7008533/
[22] Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med [Internet]. 1 de febrero de 2020 [citado 28 de enero de 2024];22(2):245. Disponible en: /pmc/articles/PMC7313390/
[23] Baalmann N, Spielmann M, Gillessen- Kaesbach G, Hanker B, Schmidt J, Lill CM, et al. Phenotypic specificity in patients with neurodevelopmental delay does not correlate with diagnostic yield of trio-exome sequencing. Eur J Med Genet. 1 de julio de 2023;66(7):104774.
[24] Danecek P, Gardner EJ, Fitzgerald TW, Gallone G, Kaplanis J, Eberhardt RY, et al. Detection and characterisation of copy number variants from exome sequencing in the DDD study. Genetics in Medicine Open [Internet]. 28 de enero de 2024 [citado 27 de febrero de 2024];101818. Disponible en: https://linkinghub.elsevier.com/retrieve/pii/S2949774424009646
[25] João S, Quental R, Pinto J, Almeida C, Santos H, Dória S. Impact of copy number variants in epilepsy plus neurodevelopment disorders. Seizure - European Journal of Epilepsy [Internet]. 1 de abril de 2024 [citado 3 de febrero de 2024];117:6-12. Disponible en: http://www.seizure-journal.com/article/S1059131124000165/fulltext
[26] Buttermore E, Chamberlain S, Cody J, Costain G, Dang L, DeWoody A, et al. Neurodevelopmental copy-number variants: A roadmap to improving outcomes by uniting patient advocates, researchers, and clinicians for collective impact. Am J Hum Genet [Internet]. 8 de agosto de 2022 [citado 28 de enero de 2024];109(8):1353. Disponible en:/pmc/articles/PMC9388383/
[27] Siracusano M, Riccioni A, Frattale I, Arturi L, Dante C, Galasso C, et al. Cognitive, adaptive and behavioral profile in Sotos syndrome children with 5q35 microdeletion or intragenic variants. Am J Med Genet A [Internet]. 1 de julio de 2023 [citado 27 de enero de 2024];191(7):1836-48. Disponible en: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.63211
[28] Orphanet: Deleción 5q35 [Internet]. [citado 28 de enero de 2024]. Disponible en: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=ES&Expert=1627
[29] Nuclear Receptor-Bindig Set Domain Protein 1; NSD1 - OMIM 606681 [Internet]. [citado 27 de enero de 2024]. Disponible en: https://www.omim.org/entry/606681
[30] Loeza-Sierra HA, López-Santos HA, Castro-Coyotl DM. Fenotipo clínico mixto de deleción y duplicación de la región del síndrome de Sotos: microdeleción 5q35.2-q35.3 detectada por microarreglo de hibridación genómica comparativa. Bol Med Hosp Infant Mex [Internet]. 2021 [citado 27 de enero de 2024];78(5):489-94. Disponible en: www.bmhim.com
[31] González-Rodríguez JD, Inglés-Torres EQ, Cabrera-Sevilla JE, Ibáñez-Micó S, Bermejo-Costa F, Vera-Carbonell A, et al. Sotos Syndrome and Nephrocalcinosis, a Rare But Possible Association due to Impact on Contiguous Genes. J Clin Res Pediatr Endocrinol [Internet]. 10 de agosto de 2023 [citado 6 de mayo de 2024]; Disponible en: https://pubmed.ncbi.nlm.nih.gov/37559368/
[32] Lin W De, Wang CH, Tsai FJ, Chou IC. Phenotype and genotype in a Taiwanese girl with Sotos Syndrome. Biomedicine (Taipei) [Internet]. 2022 [citado 6 de mayo de 2024];12(3):5. Disponible en: /pmc/articles/PMC9629404/
[33] Schwaibold EMC, Beygo J, Obeid K, Jauch A, Hinderhofer K, Moog U. A boy with Silver–Russell syndrome and Sotos syndrome. Am J Med Genet A [Internet]. 1 de febrero de 2021 [citado 28 de enero de 2024];185(2):549-54. Disponible en: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.61967
[34] Calcagni G, Ferrigno F, Franceschini A, Dentici ML, Capolino R, Sinibaldi L, et al. Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome. Diagnostics 2024, Vol 14, Page 594 [Internet]. 11 de marzo de 2024 [citado 6 de mayo de 2024];14(6):594. Disponible en: https://www.mdpi.com/2075-4418/14/6/594/htm
[35] Van der Lugt NM, Weerts MJA, Veenma DCM, Lincke CR, Gischler SJ, Alders M, et al. 5q35 duplication syndrome: Narrowing the critical region on the distal side and further evidence of intrafamilial variability and expression. Am J Med Genet A [Internet]. 1 de marzo de 2023 [citado 27 de enero de 2024];191(3):835-41. Disponible en: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.63068
[36] Quintero-Rivera F, Eno CC, Sutanto C, Jones KL, Nowaczyk MJM, Wong D, et al. 5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation. Hum Genet [Internet]. 1 de abril de 2021 [citado 27 de enero de 2024];140(4):681. Disponible en: /pmc/articles/PMC8733961/
[37] Wilczewski CM, Obasohan J, Paschall JE, Zhang S, Singh S, Maxwell GL, et al. Genotype first: Clinical genomics research through a reverse phenotyping approach. Am J Hum Genet [Internet]. 5 de enero de 2023 [citado 18 de mayo de 2024];110(1):3-12. Disponible en: http://www.cell.com/article/S0002929722005389/fulltext
[38] AlphaFold Protein Structure Database [Internet]. [citado 8 de junio de 2024]. Disponible en: https://alphafold.ebi.ac.uk/entry/A0A3G1LEI2
[39] Understanding Gene Interactions Holds Key to Personalized Medicine, Donnelly Centre Scientists Say | Donnelly Centre for Cellular and Biomolecular Research [Internet]. [citado 8 de junio de 2024]. Disponible en: https://thedonnellycentre.utoronto.ca/news/understanding-gene-interactions-holds-key-personalized-medicine-donnelly-centre-scientists-say
[40] NSD1 (Homo sapiens) - STITCH network view [Internet]. [citado 8 de junio de 2024]. Disponible en: http://stitch.embl.de/cgi/network.pl?taskId=unhR106rsaRJ
[41] GeneMANIA [Internet]. [citado 8 de junio de 2024]. Disponible en: https://genemania.org/search/homo-sapiens/DDX41/F12/NSD1/SLC34A1/SNCB/FGFR4
[2] Xu C, Li M, Gu T, Xie F, Zhang Y, Wang D, et al. Chromosomal microarray analysis for prenatal diagnosis of uniparental disomy: a retrospective study. Mol Cytogenet [Internet]. 1 de diciembre de 2024 [citado 17 de febrero de 2024];17(1):1-7. Disponible en: https://molecularcytogenetics.biomedcentral.com/articles/10.1186/s13039-023-00668-8
[3] Qian G, Cai L, Yao H, Dong X. Chromosome microarray analysis combined with karyotype analysis is a powerful tool for the detection in pregnant women with high-risk indicators. BMC Pregnancy Childbirth [Internet]. 1 de diciembre de 2023 [citado 17 de febrero de 2024];23(1):1-7. Disponible en: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-023-06052-z
[4] Savatt JM, Myers SM. Genetic Testing in Neurodevelopmental Disorders. Front Pediatr. 19 de febrero de 2021;9:526779.
[5] Zhang L, Tie X, Che F, Wang G, Ge Y, Li B, et al. Novel maternal duplication of 6p22.3-p25.3 with subtelomeric 6p25.3 deletion: new clinical findings and genotype–phenotype correlations. Mol Cytogenet [Internet]. 1 de diciembre de 2023 [citado 28 de enero de 2024];16(1):11. Disponible en: /pmc/articles/PMC10259020/
[6] Wu D, Wu Y, Lan Y, Lan S, Zhong Z, Li D, et al. Chromosomal Aberrations in Pediatric Patients With Moderate/Severe Developmental Delay/Intellectual Disability With Abundant Phenotypic Heterogeneities: A Single-Center Study. Pediatr Neurol [Internet]. 1 de octubre de 2023 [citado 17 de febrero de 2024];147:72-81. Disponible en: http://www.pedneur.com/article/S088789942300173X/fulltext
[7] Lalonde E, Rentas S, Lin F, Dulik MC, Skraban CM, Spinner NB. Genomic Diagnosis for Pediatric Disorders: Revolution and Evolution. Front Pediatr. 8 de julio de 2020;8:498541.
[8] Qian G, Cai L, Yao H, Dong X. Chromosome microarray analysis combined with karyotype analysis is a powerful tool for the detection in pregnant women with high-risk indicators. BMC Pregnancy Childbirth [Internet]. 1 de diciembre de 2023 [citado 17 de febrero de 2024];23(1):1-7. Disponible en: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-023-06052-z
[9] Savatt JM, Myers SM. Genetic Testing in Neurodevelopmental Disorders. Front Pediatr. 19 de febrero de 2021;9:526779.
[10] Danecek P, Gardner EJ, Fitzgerald TW, Gallone G, Kaplanis J, Eberhardt RY, et al. Detection and characterisation of copy number variants from exome sequencing in the DDD study. Genetics in Medicine Open [Internet]. 28 de enero de 2024 [citado 27 de febrero de 2024];101818. Disponible en: https://linkinghub.elsevier.com/retrieve/pii/S2949774424009646
[11] Zhang L, Tie X, Che F, Wang G, Ge Y, Li B, et al. Novel maternal duplication of 6p22.3-p25.3 with subtelomeric 6p25.3 deletion: new clinical findings and genotype–phenotype correlations. Mol Cytogenet [Internet]. 1 de diciembre de 2023 [citado 28 de enero de 2024];16(1):11. Disponible en: /pmc/articles/PMC10259020/
[12] Human hg38 chr5:176,517,339-179,570,928 UCSC Genome Browser v459 [Internet]. [citado 27 de enero de 2024]. Disponible en: https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr5%3A176517339%2D179570928&hgsid=1896488230_BSeIQBO4uuZ3glaFUKsCS45JP7iN
[13] Search - GeneScout [Internet]. [citado 2 de mayo de 2024]. Disponible en: https://genescout.omim.org/search?primaryCoordinates=chr5%3A176517339-179570928&assembly=GRCh38&comparisonCoordinates=&operation=intersect#
[14] Ravel JM, Renaud M, Muller J, Becker A, Renard É, Remen T, et al. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study. Genome Med [Internet]. 1 de diciembre de 2023 [citado 21 de febrero de 2024];15(1):1-10. Disponible en: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-023-01191-6
[15] Sandoval-Talamantes AK, Mori MÁ, Santos-Simarro F, García-Miñaur S, Mansilla E, Tenorio JA, et al. Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital. Genes 2023, Vol 14, Page 820 [Internet]. 29 de marzo de 2023 [citado 17 de febrero de 2024];14(4):820. Disponible en: https://www.mdpi.com/2073-4425/14/4/820/htm
[16] Miceli M, Failla P, Saccuzzo L, Galesi O, Amata S, Romano C, et al. Trait - driven analysis of the 2p15p16.1 microdeletion syndrome suggests a complex pattern of interactions between candidate genes. Genes Genomics [Internet]. 1 de abril de 2023 [citado 18 de mayo de 2024];45(4):491-505. Disponible en: https://pubmed.ncbi.nlm.nih.gov/36807877/
[17] Tritto V, Eoli M, Paterra R, Redaelli S, Moscatelli M, Rusconi F, et al. Characterization of 22q12 Microdeletions Causing Position Effect in Rare NF2 Patients with Complex Phenotypes. Int J Mol Sci [Internet]. 1 de septiembre de 2022 [citado 18 de mayo de 2024];23(17). Disponible en: /pmc/articles/PMC9456353/
[18] Micale L, Morlino S, Carbone A, Carissimo A, Nardella G, Fusco C, et al. Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement. Genet Med [Internet]. 1 de febrero de 2022 [citado 18 de mayo de 2024];24(2):439-53. Disponible en: https://pubmed.ncbi.nlm.nih.gov/34906501/
[19] Jønch AE, Douard E, Moreau C, Van Dijck A, Passeggeri M, Kooy F, et al. Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice. J Med Genet [Internet]. 1 de octubre de 2019 [citado 18 de mayo de 2024];56(10):701-10. Disponible en: https://pubmed.ncbi.nlm.nih.gov/31451536/
[20] Nunes N, Carvalho Nunes B, Zamariolli M, Cordeiro de Queiroz Soares D, Caires Dos Santos L, Gollo Dantas A, et al. Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome. Genet Res (Camb) [Internet]. 2024 [citado 18 de mayo de 2024];2024:5549592. Disponible en: https://pubmed.ncbi.nlm.nih.gov/38586596/
[21] Zinkstok JR, Boot E, Bassett AS, Hiroi N, Butcher NJ, Vingerhoets C, et al. Neurobiological perspective of 22q11.2 deletion syndrome. Lancet Psychiatry [Internet]. 1 de noviembre de 2019 [citado 18 de mayo de 2024];6(11):951. Disponible en: /pmc/articles/PMC7008533/
[22] Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med [Internet]. 1 de febrero de 2020 [citado 28 de enero de 2024];22(2):245. Disponible en: /pmc/articles/PMC7313390/
[23] Baalmann N, Spielmann M, Gillessen- Kaesbach G, Hanker B, Schmidt J, Lill CM, et al. Phenotypic specificity in patients with neurodevelopmental delay does not correlate with diagnostic yield of trio-exome sequencing. Eur J Med Genet. 1 de julio de 2023;66(7):104774.
[24] Danecek P, Gardner EJ, Fitzgerald TW, Gallone G, Kaplanis J, Eberhardt RY, et al. Detection and characterisation of copy number variants from exome sequencing in the DDD study. Genetics in Medicine Open [Internet]. 28 de enero de 2024 [citado 27 de febrero de 2024];101818. Disponible en: https://linkinghub.elsevier.com/retrieve/pii/S2949774424009646
[25] João S, Quental R, Pinto J, Almeida C, Santos H, Dória S. Impact of copy number variants in epilepsy plus neurodevelopment disorders. Seizure - European Journal of Epilepsy [Internet]. 1 de abril de 2024 [citado 3 de febrero de 2024];117:6-12. Disponible en: http://www.seizure-journal.com/article/S1059131124000165/fulltext
[26] Buttermore E, Chamberlain S, Cody J, Costain G, Dang L, DeWoody A, et al. Neurodevelopmental copy-number variants: A roadmap to improving outcomes by uniting patient advocates, researchers, and clinicians for collective impact. Am J Hum Genet [Internet]. 8 de agosto de 2022 [citado 28 de enero de 2024];109(8):1353. Disponible en:/pmc/articles/PMC9388383/
[27] Siracusano M, Riccioni A, Frattale I, Arturi L, Dante C, Galasso C, et al. Cognitive, adaptive and behavioral profile in Sotos syndrome children with 5q35 microdeletion or intragenic variants. Am J Med Genet A [Internet]. 1 de julio de 2023 [citado 27 de enero de 2024];191(7):1836-48. Disponible en: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.63211
[28] Orphanet: Deleción 5q35 [Internet]. [citado 28 de enero de 2024]. Disponible en: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=ES&Expert=1627
[29] Nuclear Receptor-Bindig Set Domain Protein 1; NSD1 - OMIM 606681 [Internet]. [citado 27 de enero de 2024]. Disponible en: https://www.omim.org/entry/606681
[30] Loeza-Sierra HA, López-Santos HA, Castro-Coyotl DM. Fenotipo clínico mixto de deleción y duplicación de la región del síndrome de Sotos: microdeleción 5q35.2-q35.3 detectada por microarreglo de hibridación genómica comparativa. Bol Med Hosp Infant Mex [Internet]. 2021 [citado 27 de enero de 2024];78(5):489-94. Disponible en: www.bmhim.com
[31] González-Rodríguez JD, Inglés-Torres EQ, Cabrera-Sevilla JE, Ibáñez-Micó S, Bermejo-Costa F, Vera-Carbonell A, et al. Sotos Syndrome and Nephrocalcinosis, a Rare But Possible Association due to Impact on Contiguous Genes. J Clin Res Pediatr Endocrinol [Internet]. 10 de agosto de 2023 [citado 6 de mayo de 2024]; Disponible en: https://pubmed.ncbi.nlm.nih.gov/37559368/
[32] Lin W De, Wang CH, Tsai FJ, Chou IC. Phenotype and genotype in a Taiwanese girl with Sotos Syndrome. Biomedicine (Taipei) [Internet]. 2022 [citado 6 de mayo de 2024];12(3):5. Disponible en: /pmc/articles/PMC9629404/
[33] Schwaibold EMC, Beygo J, Obeid K, Jauch A, Hinderhofer K, Moog U. A boy with Silver–Russell syndrome and Sotos syndrome. Am J Med Genet A [Internet]. 1 de febrero de 2021 [citado 28 de enero de 2024];185(2):549-54. Disponible en: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.61967
[34] Calcagni G, Ferrigno F, Franceschini A, Dentici ML, Capolino R, Sinibaldi L, et al. Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome. Diagnostics 2024, Vol 14, Page 594 [Internet]. 11 de marzo de 2024 [citado 6 de mayo de 2024];14(6):594. Disponible en: https://www.mdpi.com/2075-4418/14/6/594/htm
[35] Van der Lugt NM, Weerts MJA, Veenma DCM, Lincke CR, Gischler SJ, Alders M, et al. 5q35 duplication syndrome: Narrowing the critical region on the distal side and further evidence of intrafamilial variability and expression. Am J Med Genet A [Internet]. 1 de marzo de 2023 [citado 27 de enero de 2024];191(3):835-41. Disponible en: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.63068
[36] Quintero-Rivera F, Eno CC, Sutanto C, Jones KL, Nowaczyk MJM, Wong D, et al. 5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation. Hum Genet [Internet]. 1 de abril de 2021 [citado 27 de enero de 2024];140(4):681. Disponible en: /pmc/articles/PMC8733961/
[37] Wilczewski CM, Obasohan J, Paschall JE, Zhang S, Singh S, Maxwell GL, et al. Genotype first: Clinical genomics research through a reverse phenotyping approach. Am J Hum Genet [Internet]. 5 de enero de 2023 [citado 18 de mayo de 2024];110(1):3-12. Disponible en: http://www.cell.com/article/S0002929722005389/fulltext
[38] AlphaFold Protein Structure Database [Internet]. [citado 8 de junio de 2024]. Disponible en: https://alphafold.ebi.ac.uk/entry/A0A3G1LEI2
[39] Understanding Gene Interactions Holds Key to Personalized Medicine, Donnelly Centre Scientists Say | Donnelly Centre for Cellular and Biomolecular Research [Internet]. [citado 8 de junio de 2024]. Disponible en: https://thedonnellycentre.utoronto.ca/news/understanding-gene-interactions-holds-key-personalized-medicine-donnelly-centre-scientists-say
[40] NSD1 (Homo sapiens) - STITCH network view [Internet]. [citado 8 de junio de 2024]. Disponible en: http://stitch.embl.de/cgi/network.pl?taskId=unhR106rsaRJ
[41] GeneMANIA [Internet]. [citado 8 de junio de 2024]. Disponible en: https://genemania.org/search/homo-sapiens/DDX41/F12/NSD1/SLC34A1/SNCB/FGFR4
Copyright © 2025 David Posada Bernal, Nathalie Yepes Madrid, Lina Johanna Moreno Giraldo
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
