Phenotypic characterization of chromosome 22 rearrangement

ABSTRACT

Chromosomal rearrangement can lead to altered gene dosage, resulting in genomic disorder. Most of chromosomal rearrangements are associated with congenital malformations and mental retardation. Therefore genomic disorders have a large impact on human health. The present study focus on chromosome 22 as a model for chromosomal rearrangement, because of its susceptibility to genomic instability. We aim to describe and clarify the associated phenotypic changes of patients with chromosome 22 rearrangement using data of our patients and others of literature. We attempt to identify the role of various 22q regions in human development and phenotype. The present study included 8 patients. They were selected among patients referred to the Clinical Genetics Department, NRC. They were representing different numerical and structural chromosome 22 rearrangements. Thorough clinical, cytogenetic and FISH studies were provided. The phenotypic manifestations were analyzed and evaluated according to the specific rearrangement. The 22q13 deletion was represented by 2 patients, displaying ring 22 and simple deletion. We observed that overall developmental delay, severe impairment of language, microcephaly, convulsions and or EEG changes were the overlapping findings among the two patients. More severe phenotypic manifestation were exhibited by patient of simple deletion, which could be the consequence of large deletion. Patient of ring 22 exhibited multiple. caf‚ au lait spots, sensorineural hearing loss and brain cyst which are consistent findings in NF2 [MIM 114570]. Disruption of NF2 gene at 22q11.21-q13.1 was highly suggestive in our patients of 22q13 deletion. Patients of NF2 should be investigated for chromosome 22q simple or cryptic deletion. Partial trisomy of chromosome 22 resulting from an interstitial duplication of 22q11.2 was represented by a patient. She exhibited cat eye syndrome [CES] phenotype [MIM 115470]. It strengthens the suggestion that trisomy of cat eye critical region [CECR] [22q11.2] is sufficient to cause CES with variable clinical findings. Paracentric inversion [PAI] of chromosome 22 was represented by 4 patients, two of them were sibs. PAI was paternally inherited, 3 patients carried the identical inversion of the phenotypically normal fathers. Non identical inversion was disclosed in one of both sibs. He exhibited congenital heart disease, one of his breakpoints was involved in 22q11.2 region. Deletion of 22q11.2 region had not been detected by conventional FISH studies in our patient. It might be explained by a small deletion that had not been detected by routine FISH studies resulting from unbalanced molecular recombinant from unequal crossing over in the inverted sequence. Further molecular studies may facilitate the identification of genes involved in cardiac morphogenesis. Unexplained mental retardation/delayed motor and mental development, abnormal facies, convulsions/EEG changes and hearing defects could be attributed to missed chromosome 22 rearrangement, particularly PAI. Our ascertainment of 7 cases with different chromosome 22 rearrangement, we observed that abnormal ear development and or hearing deficiency was a constant and common clinical finding among our patients. In general, chromosome 22 may play an important role in ear and hearing development in human. In particular, genomic disorder of 22q11.2 region has a major role in cardiac morphogenesis and CES phenotypes