Apparent Homozygosity of p.Phe508del inCFTRdue to a Large Gene Deletion of Exons 4–11

Abstract

We report a classic cystic fibrosis (CF) boy with a large deletion of exons 4–11 in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on one allele and p.Phe508del in exon 10 on the second allele. Both parents of Georgian and Ukrainian background had no personal or family history of the disease. The initial molecular diagnostic investigation identified the patient as homozygous for the p.Phe508del and not compatible with his parent's genetic status. The possibility of nonpaternity or uniparental disomy (UPD7) was investigated and excluded using microsatellite analysis of highly polymorphic markers on chromosome 7. Array-CGH was also performed on the patient and revealed a male profile with a subtle deletion within the CFTR gene on the long arm (q-arm) of chromosome 7 (7q31.2). The deletion was confirmed by MLPA extending from probe L02380 to probe L14978 (28.7 kb) and that was inherited from his father, while p.PheF508del was inherited from his mother. These data highlight the need for additional testing for large deletions in patients with apparent homozygosity for a mutated CFTR allele that do not match the carrier status of the parents. Not testing can lead to misdiagnosis and misinterpretation of mutation carrier status and the expected penetrance of the disorder.

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

“…Some symptomatic patients carry only one detectable mutation in one CFTR allele and a large deletion on the other, but because this last event cannot be detected by standard techniques, some patients have been diagnosed as apparently homozygous for the detectable mutation. 12 Moreover, since these methods are unable to detect single or multiple exonic rearrangements, the frequency of such events is not well established. Historically, most of the large deletions in CFTR in patients with CF were identified by coincidence, either by noting a uniparental inheritance pattern or through failure of PCR amplification.…”

Apparent homozygosity due to compound heterozygosity of one point mutation and an overlapping exon deletion mutation in ABCA12: A genetic diagnostic pitfall

“…This combination of mutations may lead us to conclude incorrectly that the patient has a homozygous point mutation, a phenomenon called "apparent homozygosity [7]". Apparent homozygosity has been reported mainly in the cystic fibrosis transmembrane conductance regulator gene which causes cystic fibrosis [7,[16][17][18]. To date, cases of apparent homozygosity have been reported in a small number of other molecules/diseases, lysosomal enzyme acid alpha-glucosidase which causes glycogen storage disease type 2 [19], arylsulfatase B which causes mucopolysaccharidosis [20], gamma-sarcoglycan which causes gamma-sarcooglycanopathy [21], and glucocerebrosidase which causes Gaucher disease [22].…”

Advantage of Genetic Modifications Using Genome Editing Technology in Stem Cells vs. Zygotes in Genetic Diseases

“…One should be selective in using genome editing in cases of monogenic disease and use it only where it appears that the benefit of using will be greater than that involved in using the appropriate genetic interventions or its side effects. For e.g., if there is evidence of inheritance very likely, because there is an autonomous recessive disease with both parents being homozygous for e.g., cystic fibrosis [40], or phenylketonuria [41], or if there is an autosomal dominant disease with one parent atleast being homozygous and affected, i.e., Huntington's disease, familial adenomatous polyposis [42], one needs to consider using it.…”