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: CFTR gene; chromosome microarray analysis; copy number variation; cystic fibrosis; loss of heterozygosity; uniparental disomy.

Fig. 1

Detailed view of the homozygous microdeletion found in the patient. A 218-kb homozygous microdeletion ( dark red rectangle ) was found on chromosome 7q31.2. The purple rectangle shows a loss of heterozygosity (LOH) region. The dark green vertical lines represent nonpolymorphic markers, and the light green vertical lines represent the polymorphic (SNP) markers. The genes are shown in pink.

Fig. 2

Molecular testing for CFTR mutations by amplification-refractory mutation system/polymerase chain reaction (ARMS-PCR). Blood samples of the patient́s mother ( A ) and father ( B ) were tested by ARMS-PCR. The bands were obtained by electrophoresis in a 2% agarose gel. A normal control was run with the parent́s samples. In the case of the mother, a heterozygous p.Phe508del control was also included. A1: normal alleles for 621 + 1G →T (380 bp), p.Asn1303Lys (328 bp) and p.Phe508del (157 bp). A2: mutant alleles for 621 + 1G →T (380 bp), p.Asn1303Lys (328 bp) and p.Phe508del (157 bp). C: normal allele for 3659 Del C (294 bp) and mutant allele for 1717–1G →A (220 bp). D: mutant allele for 3659 Del C (294 bp) and normal allele for 1717–1G →A (220 bp).

Fig. 3

Detailed view of the microdeletions found in patient and mother. A 218-kb heterozygous microdeletion ( light red rectangle ) was found in the patient's mother. This copy number variation (CNV) is the same as the one found in the child in a homozygous state ( dark red rectangle ) on chromosome 7q31.2. The purple rectangle shows a loss of heterozygosity (LOH) region. The dark green lines are nonpolymorphic markers, and the light green lines represent the polymorphic (SNP) markers. The genes are shown in pink .

Fig. 4

Possible explanation of the patient's interstitial maternal isodisomy formation. An error during maternal meiosis II may have given rise to the formation of a trisomy 7 zygote, containing the two maternal affected sister chromatids. After fertilization, a mitotic double crossing-over between two nonuniparental chromatids took place, forming a paternal chromosome containing a maternally derived interstitial segment that carried the deleted CFTR region. Subsequently, and due to trisomy rescue, the maternal chromatid involved in the exchange was lost. The red rectangle indicates the deleted CFTR region. The black circle indicates the centromeres.