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HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ

Yıl 2021, Cilt: 22 Sayı: 4, 253 - 260, 01.07.2021
https://doi.org/10.18229/kocatepetip.731084

Öz

AMAÇ: Hipotoni, uzuvlarda, gövdede veya kraniyofasiyal iskelet kaslarında azalmış tonusu belirtmek için kullanılan genel bir terimdir. Doğumda veya daha sonra çocukluk döneminde tespit edilebilir. Tanıyı koymak, prognozu öngörebilmek, tedavi stratejileri ve ailenin daha sonra doğacak çocukları için tekrarlama riskini belirlemek açısından önemlidir. Nörolojik muayene ve beyin görüntülemesine ek olarak konvansiyonel sitogenetik, moleküler sitogenetik ve moleküler genetik testler klinik tanıyı desteklemek açısından önemlidir. Hipotoni, minor veya major malformasyonlarla ve bilişsel yetersizlik ile birlikte olduğu zaman otozomal kromozom anormallikleri düşünülmelidir. Aralarında klinik farklılıklar bulunan değişik kromozom anormallikleri ve sendromlarda atipik yüz görünümü, el ve ayakta dismorfik bulgular veya diğer organ malformasyonları bulunabilir. Genetik testlerdeki son gelişmeler, moleküler tanıların daha da genişleyen yelpazesi spinal müsküler atrofi, konjenital miyotonik distrofi, Prader-Willi sendromu ile hastalık altında yatan mutasyonların (konjenital kas distrofileri ve birkaç konjenital miyopati) tanımlanması, bu semptomu olan çocuklara spesifik tanı imkanı sağlar.
GEREÇ VE YÖNTEM: Çalışmamıza Trakya Üniversitesi Hastanesi, Tıbbi Genetik Anabilim Dalı, Genetik Hastalıklar Tanı Merkezi polikliniğine 2017-2019 yılları arasında hipotoni klinik ön tanısı ile birlikte müracaat eden 47 çocuk hasta dâhil edildi. Hasta genomik DNA’ları ile array-karşılaştırmalı genomik hibridizasyon (aCGH) çalışması gerçekleştirildi.
BULGULAR: 47 hastanın 12’sinde (%25,53) 557kb ila 40 Mb arası büyüklükte kopya sayısı değişimleri (CNV) saptandı. Tespit edilen kopya sayısı varyantları, Genomik Varyantlar Veritabanı (DGV), Ensembl kaynakları Genomik Varyasyon ve Fenotip Veritabanı (DECIPHER), Sitogenomik Diziler için Uluslararası Standartlar (ISCA) ve Klinik olarak ilgili varyant veritabanlarının yorumlarının genel arşivi veritabanları ile literatür taramalarından araştırılarak değerlendirilmiştir.
SONUÇ: Yenidoğan ve infantil dönemde hipotoni nedenleri arasında yer alan tablolar, genetik sendromlar, kas hastalıkları, kranial malformasyonlar, metabolik hastalıklar özellikle peroksizomal ve mitokondriyal hastalıklardır. Bu grup hastalıklar arasında ayırıcı tanısı yapabilmek için EMG, Kranial MR ve kas biopsisi gibi invazif testler uygulanır. Sonuç olarak, yenidoğan ve infantil döneminde ciddi hipotoni varlığında hastanın genetik açıdan değerlendirilmesi, sebebi bilinmeyen hipotoninin nedenini oluşturan pek çok hastalığın tanısı için yapılacak gereksiz invasif testlerin yükünden hastayı kurtarabilir. Erken tanı, ayrıca, hastalığa özgü ortaya çıkabilecek problemlerden korunma ve erken tedavisi açısından da bir o kadar önemlidir. Hastalığın erken dönemde tanısını koymak, hastanın rehabilitasyonuna daha erken başlama imkânı sağlayacağından önem arz etmektedir.

Kaynakça

  • 1. Lisi EC, Cohn RD. Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature. Dev Med Child Neurol 2011;53(7):586-99.
  • 2. Tansuğ N. Hipotonik infant. Türkiye Klinikleri J Pediatr – Special Topics 2004;2(7):763-772.
  • 3. Gowda, V, Parr, J, Jayawant, S. Evaluation of the floppy infant. Pediatr Child Health 2008; 18:17–21.
  • 4. Aydın K. Hipotonik yenidoğanın değerlendirilmesi. Sendrom Dergisi: Yenidoğan Özel Sayısı 2007; 19 (11): 139-142.
  • 5. Karaali Savrun F, Uzun N, Kızıltan M. Hipotonik bebeklerin elektrofizyolojik değerlendirilmesi. Yeni Symposium 2001; 39 (2): 70-73.
  • 6. Wang Y, Peng W, Guo HY, et al. Next-generation sequencing-based molecular diagnosis of neonatal hypotonia in Chinese Population. Sci Rep 2016; 6:288-290.
  • 7. Koolen DA, Vissers LE, Pfundt R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 2006;38(9):999-1001.
  • 8. Phelan, M.C. Deletion 22q13.3 syndrome. Orphanet J Rare Dis 2008;3, 14.
  • 9. Lu XY, Phung MT, Shaw CA, et al. Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics 2008;122(6):1310-1318.
  • 10. Preka E, Paoloni-Giacobino A, Sloan-Béna F et al. Atypical Hypotonia-Cystinuria a New Case: Genotype-Phenotype, Description. J Genet Disor Genet Rep 2018; 7:3.
  • 11. Lister Hill National Center for Biomedical Communications U.S. National Library of Medicine Published: May 26, 2020, https://ghr.nlm.nih.gov/condition/22q133-deletion-syndrome.
  • 12. Phelan K, McDermid HE. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol Syndromol 2012;2(3-5):186-201.
  • 13. Krgovic D, Blatnik A, Burmas A, Zagorac A, Kokalj Vokac N. A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5. BMC Med Genet 2014; 15:21.
  • 14. Velagaleti GV, Morgan DL, Tonk VS. Trisomy 5p. A case report and review. Ann Genet 2000;43(3-4):143-145.
  • 15. Roberson ED, Wohler ES, Hoover-Fong JE, et al. Genomic analysis of partial 21q monosomies with variable phenotypes. Eur J Hum Genet 2011;19(2):235-238.
  • 16. Hussein IR, Bassiouni R, Chaudhary A, Malki A, Alqahtani M. Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies. Journal of Molecular Biomarkers & Diagnosis 6 (2015): 1-7.
  • 17. National Organization for Rare Disorders (NORD) 2009. https://rarediseases.org/rare-diseases/chromosome-4-monosomy-distal-4q/
  • 18. Milone R, Valetto A, Battini R, et al. Focal cortical dysplasia, microcephaly and epilepsy in a boy with 1q21.1-q21.3 duplication. Eur J Med Genet 2016;59(5):278-282.
  • 19. Goizet C, Coupry I, Rooryck C, et al. Molecular characterization of an 11q14.3 microdeletion associated with leukodystrophy. Eur J Hum Genet 2004;12(3):245-250.
  • 20. Papoulidis I, Paspaliaris V, Siomou E, et al. Interstitial deletion at 11q14.2-11q22.1 may cause severe learning difficulties, mental retardation and mild heart defects in 13-year old male. Mol Cytogenet 2015; 8:71.
  • 21. Understanding Chromosome Disorders. Rare Chromosome Disorder Support Group,2007.https://www.rarechromo.org/media/information/Chromosome%2014/14q%20distal%20duplications%20FTNW.pdf Erişim: 13.02.2020
  • 22. Lister Hill National Center for Biomedical Communications U.S. National Library of Medicine 2020. https://ghr.nlm.nih.gov/condition/2q37-deletion-syndrome Erişim: 21.02.2020
  • 23. Brecevic L, Rincic M, Krsnik Z, et al. Association of new deletion/duplication region at chromosome 1p21 with intellectual disability, severe speech deficit and autism spectrum disorder-like behavior: an all-in approach to solving the DPYD enigma. Transl Neurosci 2015;6(1):59-86.
  • 24. Belengeanu, V, Gug C, Belengeanu A. Partial duplication (1)(p22.1p31.1) report on a boy with mental retardation, abnormal genitalia and absent patellae. TMJ 2005;55:3.
  • 25. Zhou HF, O'Conor CJ, Gangahar C, Dehner LP. 15q23 Gain in a Neonate with a Giant Omphalocele and Multiple Co-Occurring Anomalies. Case Rep Pediatr 2018; 2018:8702568.
  • 26. Van Bon BW, Mefford HC, Menten B, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009;46(8):511-523.
  • 27. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 2009;46(4):242-248.
  • 28. Petti M, Samanich J, Pan Q, et al. Molecular characterization of an interstitial deletion of 1p31.3 in a patient with obesity and psychiatric illness and a review of the literature. Am J Med Genet A 2011;155A (4):825-832.

THE IMPORTANCE OF GENOME COPY NUMBER VARIATIONS IN CHILDREN WITH A DIAGNOSIS OF HYPOTONIA

Yıl 2021, Cilt: 22 Sayı: 4, 253 - 260, 01.07.2021
https://doi.org/10.18229/kocatepetip.731084

Öz

OBJECTIVE: Hypotonia is a general term used to denote reduced tone in the limbs, trunk, or craniofacial skeletal muscles. It can be detected at birth or later in childhood. It is important to establish the diagnosis, predict the prognosis, determine treatment strategies and the risk of recurrence for later generations of the family. In addition to neurological examination and brain imaging, conventional cytogenetics, molecular cytogenetics and molecular genetic tests are important to support clinical diagnosis. Autosomal chromosome abnormalities should be considered when combined with hypotonia, minor or major malformations and cognitive impairment. A variety of chromosome abnormalities and syndromes, including clinical differences, may include atypical facial appearance, hand and foot dysmorphic findings or other organ malformations. Recent advances in genetic testing, expanding spectrum of molecular diagnostics, spinal muscular atrophy, congenital myotonic dystrophy, identification of underlying mutations (congenital muscular dystrophies and several congenital myopathies) with Prader-Willi syndrome, provide a specific diagnosis for children with this symptom.

MATERIAL AND METHODS: 47 children who applied to the Trakya University Hospital, Medical Genetics Department, Genetic Diseases Diagnosis Center clinic with a pre-diagnosis of hypotonia between 2017-2019 were included in our study. Array-comparative genomic hybridization (aCGH) study was performed with patient genomic DNA.
RESULTS: Copy number variations (CNV) in the size of 557kb to 40 Mb was detected in 12 of 47 patients (25.53%). The detected CNVs were researched and evaluated from the literature searches after Database of Genomic Variants (DGV), Database of genomic variation and phenotype in humans using Ensembl Resources (DECIPHER), International Standards for Cytogenomic Arrays and Public archive (ISCA) of interpretations of clinically relevant variants databases.
CONCLUSIONS: Conditions that are among the causes of hypotonia in newborn and infantile periods are genetic syndromes, muscle diseases, cranial malformations, metabolic diseases, especially peroxisomal and mitochondrial diseases. In order to make a differential diagnosis among this group of diseases, invasive tests such as EMG, Cranial MR and muscle biopsy are applied. As a result, in the presence of severe hypotonia in the neonatal and infantile period, the genetic evaluation of the patient can save the patient from the burden of unnecessary invasive tests for the diagnosis of many diseases that are the cause of the unknown hypotonia. Early diagnosis is also important in terms of prevention and early treatment of problems that may arise specific to the disease. It is important to diagnose the disease in the early period, as it will allow the patient to start rehabilitation earlier.

Kaynakça

  • 1. Lisi EC, Cohn RD. Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature. Dev Med Child Neurol 2011;53(7):586-99.
  • 2. Tansuğ N. Hipotonik infant. Türkiye Klinikleri J Pediatr – Special Topics 2004;2(7):763-772.
  • 3. Gowda, V, Parr, J, Jayawant, S. Evaluation of the floppy infant. Pediatr Child Health 2008; 18:17–21.
  • 4. Aydın K. Hipotonik yenidoğanın değerlendirilmesi. Sendrom Dergisi: Yenidoğan Özel Sayısı 2007; 19 (11): 139-142.
  • 5. Karaali Savrun F, Uzun N, Kızıltan M. Hipotonik bebeklerin elektrofizyolojik değerlendirilmesi. Yeni Symposium 2001; 39 (2): 70-73.
  • 6. Wang Y, Peng W, Guo HY, et al. Next-generation sequencing-based molecular diagnosis of neonatal hypotonia in Chinese Population. Sci Rep 2016; 6:288-290.
  • 7. Koolen DA, Vissers LE, Pfundt R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 2006;38(9):999-1001.
  • 8. Phelan, M.C. Deletion 22q13.3 syndrome. Orphanet J Rare Dis 2008;3, 14.
  • 9. Lu XY, Phung MT, Shaw CA, et al. Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics 2008;122(6):1310-1318.
  • 10. Preka E, Paoloni-Giacobino A, Sloan-Béna F et al. Atypical Hypotonia-Cystinuria a New Case: Genotype-Phenotype, Description. J Genet Disor Genet Rep 2018; 7:3.
  • 11. Lister Hill National Center for Biomedical Communications U.S. National Library of Medicine Published: May 26, 2020, https://ghr.nlm.nih.gov/condition/22q133-deletion-syndrome.
  • 12. Phelan K, McDermid HE. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol Syndromol 2012;2(3-5):186-201.
  • 13. Krgovic D, Blatnik A, Burmas A, Zagorac A, Kokalj Vokac N. A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5. BMC Med Genet 2014; 15:21.
  • 14. Velagaleti GV, Morgan DL, Tonk VS. Trisomy 5p. A case report and review. Ann Genet 2000;43(3-4):143-145.
  • 15. Roberson ED, Wohler ES, Hoover-Fong JE, et al. Genomic analysis of partial 21q monosomies with variable phenotypes. Eur J Hum Genet 2011;19(2):235-238.
  • 16. Hussein IR, Bassiouni R, Chaudhary A, Malki A, Alqahtani M. Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies. Journal of Molecular Biomarkers & Diagnosis 6 (2015): 1-7.
  • 17. National Organization for Rare Disorders (NORD) 2009. https://rarediseases.org/rare-diseases/chromosome-4-monosomy-distal-4q/
  • 18. Milone R, Valetto A, Battini R, et al. Focal cortical dysplasia, microcephaly and epilepsy in a boy with 1q21.1-q21.3 duplication. Eur J Med Genet 2016;59(5):278-282.
  • 19. Goizet C, Coupry I, Rooryck C, et al. Molecular characterization of an 11q14.3 microdeletion associated with leukodystrophy. Eur J Hum Genet 2004;12(3):245-250.
  • 20. Papoulidis I, Paspaliaris V, Siomou E, et al. Interstitial deletion at 11q14.2-11q22.1 may cause severe learning difficulties, mental retardation and mild heart defects in 13-year old male. Mol Cytogenet 2015; 8:71.
  • 21. Understanding Chromosome Disorders. Rare Chromosome Disorder Support Group,2007.https://www.rarechromo.org/media/information/Chromosome%2014/14q%20distal%20duplications%20FTNW.pdf Erişim: 13.02.2020
  • 22. Lister Hill National Center for Biomedical Communications U.S. National Library of Medicine 2020. https://ghr.nlm.nih.gov/condition/2q37-deletion-syndrome Erişim: 21.02.2020
  • 23. Brecevic L, Rincic M, Krsnik Z, et al. Association of new deletion/duplication region at chromosome 1p21 with intellectual disability, severe speech deficit and autism spectrum disorder-like behavior: an all-in approach to solving the DPYD enigma. Transl Neurosci 2015;6(1):59-86.
  • 24. Belengeanu, V, Gug C, Belengeanu A. Partial duplication (1)(p22.1p31.1) report on a boy with mental retardation, abnormal genitalia and absent patellae. TMJ 2005;55:3.
  • 25. Zhou HF, O'Conor CJ, Gangahar C, Dehner LP. 15q23 Gain in a Neonate with a Giant Omphalocele and Multiple Co-Occurring Anomalies. Case Rep Pediatr 2018; 2018:8702568.
  • 26. Van Bon BW, Mefford HC, Menten B, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009;46(8):511-523.
  • 27. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 2009;46(4):242-248.
  • 28. Petti M, Samanich J, Pan Q, et al. Molecular characterization of an interstitial deletion of 1p31.3 in a patient with obesity and psychiatric illness and a review of the literature. Am J Med Genet A 2011;155A (4):825-832.
Toplam 28 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Klinik Tıp Bilimleri
Bölüm Makaleler-Araştırma Yazıları
Yazarlar

Emine İkbal Atli 0000-0001-9003-1449

Hakan Gurkan 0000-0002-8967-6124

Damla Eker Bu kişi benim 0000-0001-7563-118X

Yayımlanma Tarihi 1 Temmuz 2021
Kabul Tarihi 8 Eylül 2020
Yayımlandığı Sayı Yıl 2021 Cilt: 22 Sayı: 4

Kaynak Göster

APA Atli, E. İ., Gurkan, H., & Eker, D. (2021). HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ. Kocatepe Tıp Dergisi, 22(4), 253-260. https://doi.org/10.18229/kocatepetip.731084
AMA Atli Eİ, Gurkan H, Eker D. HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ. KTD. Temmuz 2021;22(4):253-260. doi:10.18229/kocatepetip.731084
Chicago Atli, Emine İkbal, Hakan Gurkan, ve Damla Eker. “HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ”. Kocatepe Tıp Dergisi 22, sy. 4 (Temmuz 2021): 253-60. https://doi.org/10.18229/kocatepetip.731084.
EndNote Atli Eİ, Gurkan H, Eker D (01 Temmuz 2021) HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ. Kocatepe Tıp Dergisi 22 4 253–260.
IEEE E. İ. Atli, H. Gurkan, ve D. Eker, “HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ”, KTD, c. 22, sy. 4, ss. 253–260, 2021, doi: 10.18229/kocatepetip.731084.
ISNAD Atli, Emine İkbal vd. “HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ”. Kocatepe Tıp Dergisi 22/4 (Temmuz 2021), 253-260. https://doi.org/10.18229/kocatepetip.731084.
JAMA Atli Eİ, Gurkan H, Eker D. HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ. KTD. 2021;22:253–260.
MLA Atli, Emine İkbal vd. “HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ”. Kocatepe Tıp Dergisi, c. 22, sy. 4, 2021, ss. 253-60, doi:10.18229/kocatepetip.731084.
Vancouver Atli Eİ, Gurkan H, Eker D. HİPOTONİ TANILI ÇOCUK HASTALARDA GENOM KOPYA SAYISI VARYASYONLARININ ÖNEMİ. KTD. 2021;22(4):253-60.

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