Cytogenetic and molecular diagnosis of Fanconi anemia revealed two hidden phenotypes: Disorder of sex development and cerebro‐oculo‐facio‐skeletal syndrome

• Published in: Molecular genetics & genomic medicine Vol. 7; no. 7; pp. e00694 - n/a
• Main Authors: Ben Haj Ali, Abir, Amouri, Ahlem, Sayeb, Marwa, Makni, Saloua, Hammami, Wajih, Naouali, Chokri, Dallali, Hamza, Romdhane, Lilia, Bashamboo, Anu, McElreavey, Kenneth, Abdelhak, Sonia, Messaoud, Olfa
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2019; Wiley Periodicals, Inc; John Wiley and Sons Inc; Wiley
• Subjects: Anemia; autozygosity mapping; Breakage; Child, Preschool; Chromosomes; Cockayne Syndrome; Cockayne Syndrome - genetics; Cockayne Syndrome - pathology; Comorbidity; Congenital diseases; Consanguinity; Cytogenetics; Deformation mechanisms; Deoxyribonucleic acid; Diagnosis; Disease; Disorders of Sex Development; Disorders of Sex Development - genetics; Disorders of Sex Development - pathology; DNA; Etiology; Fanconi Anemia; Fanconi Anemia - genetics; Fanconi Anemia - pathology; Fanconi syndrome; Female; Genes; Genetic counseling; Genetic screening; Genetic Testing; Genetics; Genotype & phenotype; Health care; Humans; incidental findings; Karyotype; Life Sciences; Linkage analysis; Mitomycin C; Mutation; Original; Patients; Pedigree; Phenotype; Phenotypes; Sex; Software; whole exome sequencing; Whole Genome Sequencing; Libya; Tunisia; genetic counseling; incidental findings; autozygosity mapping; Comorbidity; whole exome sequencing
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.694

Background Several studies have shown a high rate of consanguinity and endogamy in North African populations. As a result, the frequency of autosomal recessive diseases is relatively high in the region with the co‐occurrence of two or more diseases. Methods We report here on a consanguineous Libyan family whose child was initially diagnosed as presenting Fanconi anemia (FA) with uncommon skeletal deformities. The chromosome breakage test has been performed using mitomycin C (MMC) while molecular analysis was performed by a combined approach of linkage analysis and whole exome sequencing. Results Cytogenetic analyses showed that the karyotype of the female patient is 46,XY suggesting the diagnosis of a disorder of sex development (DSD). By looking at the genetic etiology of FA and DSD, we have identified p.[Arg798*];[Arg798*] mutation in FANCJ (OMIM #605882) gene responsible for FA and p.[Arg108*];[Arg1497Trp] in EFCAB6 (Gene #64800) gene responsible for DSD. In addition, we have incidentally discovered a novel mutation p.[Gly1372Arg];[Gly1372Arg] in the ERCC6 (CSB) (OMIM #609413) gene responsible for COFS that might explain the atypical severe skeletal deformities. Conclusion The co‐occurrence of clinical and overlapping genetic heterogeneous entities should be taken into consideration for better molecular and genetic counseling. This is the first case reported with the combination of three rare entities: Fanconi anemia (FA) associated with disorders of sex development (DSD) and cerebro‐oculo‐facial‐skeletal syndrome (COFS). This article illustrates that the main challenging consequence of comorbidity is the possibility of misdiagnosis especially when phenotypes are extremely rare and overlapping as one phenotype could be hidden by another