Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis

Abstract

We report the first case in Peru of cystic fibrosis caused by a homozygous deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A 10-month-old child who presented with meconium ileus and pancreatic insufficiency was tested for cystic fibrosis. Both parents of the child are of Peruvian background, are nonconsanguineous, and have no personal or family history of the disease. Chromosome microarray analysis revealed a homozygous deletion of the CFTR gene on chromosome 7 (7q31.2) within a maternally derived 12.8-Mb region of loss of heterozygosity with deletion of a region that includes the CFTR gene. Parental testing confirmed this finding. This case highlights the great importance of molecular testing and the study of chromosomal rearrangements in reaching a correct diagnosis and providing proper genetic counseling to the affected families.

Keywords

cystic fibrosis - CFTR gene - chromosome microarray analysis - copy number variation - loss of heterozygosity - uniparental disomy

• References

• 1 Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992; 256 (5058): 774-779
• 2 Dalemans W, Barbry P, Champigny G. , et al. Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 1991; 354 (6354): 526-528
• 3 De Boeck K, Derichs N, Fajac I. , et al; ECFS Diagnostic Network Working Group; EuroCareCF WP3 Group on CF diagnosis. New clinical diagnostic procedures for cystic fibrosis in Europe. J Cyst Fibros 2011; 10 (02) (Suppl. 02) S53-S66
• 4 Kerem B, Kerem E. The molecular basis for disease variability in cystic fibrosis. Eur J Hum Genet 1996; 4 (02) 65-73
• 5 Lukacs GL, Chang XB, Bear C. , et al. The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells. J Biol Chem 1993; 268 (29) 21592-21598
• 6 Mall MA, Hartl D. CFTR: cystic fibrosis and beyond. Eur Respir J 2014; 44 (04) 1042-1054
• 7 Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352 (19) 1992-2001
• 8 Wilschanski M. Class 1 CF mutations. Front Pharmacol 2012; 3: 117
• 9 Aquino R, Protzel A, Rivera J. , et al. Frecuencia de las mutaciones más comunes del gen CFTR en pacientes peruanos con fibrosis quística mediante la técnica ARMS-PCR. Rev Peru Med Exp Salud Publica 2017; 34 (01) 62-69
• 10 Verma R, Babu A. Human Chromosomes: Principles & Techniques. Vol. 43. 2nd ed. New York, NY: McGraw-Hill; 1995
• 11 Miller DT, Adam MP, Aradhya S. , et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86 (05) 749-764
• 12 Neocleous V, Yiallouros PK, Tanteles GA. , et al. Apparent homozygosity of p.Phe508del in CFTR due to a large gene deletion of exons 4-11. Case Rep Genet 2014; 2014: 613863
• 13 Hantash FM, Redman JB, Starn K. , et al. Novel and recurrent rearrangements in the CFTR gene: clinical and laboratory implications for cystic fibrosis screening. Hum Genet 2006; 119 (1-2): 126-136
• 14 Schneider M, Joncourt F, Sanz J, von Känel T, Gallati S. Detection of exon deletions within an entire gene (CFTR) by relative quantification on the LightCycler. Clin Chem 2006; 52 (11) 2005-2012
• 15 Chevalier-Porst F, Souche G, Bozon D. Identification and characterization of three large deletions and a deletion/polymorphism in the CFTR gene. Hum Mutat 2005; 25 (05) 504-504
• 16 Audrézet MP, Chen JM, Raguénès O. , et al. Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat 2004; 23 (04) 343-357
• 17 Niel F, Martin J, Dastot-Le Moal F. , et al. Rapid detection of CFTR gene rearrangements impacts on genetic counselling in cystic fibrosis. J Med Genet 2004; 41 (11) e118-e118
• 18 Bombieri C, Bonizzato A, Castellani C, Assael BM, Pignatti PF. Frequency of large CFTR gene rearrangements in Italian CF patients. Eur J Hum Genet 2005; 13 (05) 687-689
• 19 Pérez MM, Luna MC, Pivetta OH, Keyeux G. CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent. J Cyst Fibros 2007; 6 (03) 194-208
• 20 Kotzot D. Complex and segmental uniparental disomy (UPD): review and lessons from rare chromosomal complements. J Med Genet 2001; 38 (08) 497-507
• 21 Gerbrands LC, Haarman EG, Hankel MA, Finken MJJ. Cystic fibrosis and Silver-Russell syndrome due to a partial maternal isodisomy of chromosome 7. Clin Case Rep 2017; 5 (10) 1697-1700
• 22 Le Caignec C, Isidor B, de Pontbriand U. , et al. Third case of paternal isodisomy for chromosome 7 with cystic fibrosis: a new patient presenting with normal growth. Am J Med Genet A 2007; 143A (22) 2696-2699
• 23 Su J, Wang J, Fan X. , et al. Mosaic UPD(7q)mat in a patient with silver Russell syndrome. Mol Cytogenet 2017; 10: 36
• 24 Azzi S, Salem J, Thibaud N. , et al. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet 2015; 52 (07) 446-453
• 25 Liehr T. Cases with uniparental disomy. Available at: http://upd-tl.com/upd.html . Accessed December 10, 2018