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Editor—We report a familial pericentric inversion (PEI) of chromosome 1 (p36.3q23) in six patients with Bardet-Biedl syndrome (BBS). The proband (III.6, fig 1), an 11 year old Libyan female, was referred for chromosomal analysis because of obesity, polydactyly, and poor vision. She was clinically diagnosed as having BBS. After clinical examination and investigations of her family members, another two sibs (III.3 and III.8) and three maternal cousins (III.10, 11, 12) were ascertained as having BBS. The clinical findings in these patients are presented in table 1. Chromosomal analysis of 100 metaphase spreads using Giemsa trypsin (GTG) banding showed that the proband had PEI (1) (fig 2) with karyotype 46,XX,inv(1)(p36.3 q23). The family members with BBS (III.3, 8, 10, 11, 12) all had the same inversion with the same breakpoints, which was inherited from the phenotypically normal proband’s mother (II.4) and her sister (II.6) (fig 1).
Pericentric inversions (PEI) have been observed in all chromosomes except chromosome 20. Different chromosomes and breakpoints are involved non-randomly.1 The prevalence of inversions varies between 0.3 and 5.0 per 1000. It was estimated to be 1.4/1000 by the French collaborative study based on the analysis of 305 cases of inversions among 221 263 karyotypes.2 The present study reports the first case of PEI (1) with breakpoints at (p36.3q23) and it is one of the largest reported inversions (involving about 64% of the total length of chromosome 1). Most of the reported cases of PEI (1) were ascertained because of male infertility.3-5 These inversions involved different breakpoints with no clear relationship between the specific chromosomal breakpoints and the degree of spermatogenic failure.6 A few cases of PEI (1) have been associated with multiple congenital anomalies or developmental delay, such as Goldenhar syndrome (p13q21),7 Fanconi anaemia (p13q21),8 mucopolysaccharidoses (p13q23),9and microtia, cleft palate, and meningomyelocele (p36.3q42).10
BBS is an autosomal recessive disorder characterised by mental retardation, obesity, pigmentary retinal dystrophy, postaxial polydactyly, and hypogenitalism. Hypertension, diabetes mellitus, and renal and cardiac abnormalities have frequently been observed.11 Previous clinical suggestions of heterogeneity in BBS were recently confirmed by the identification of four different chromosome loci linked to the disease on chromosomes 3p13 (BBS3), 11q13 (BBS1), 15q22.3q23 (BBS4), and 16q21 (BBS2, MIM 209900 and 209901),12-14 but some families failed to show linkage to any of these loci.15 Beales et al 15 came to the conclusion that the lack of established linkage in four consanguineous families (28% of their study) from the Middle East and Asia to any of the four BBS loci suggests the presence of at least a fifth BBS locus, and it would seem that locus distribution is subject to regional variation. They also added that the most promising strategy for identifying BBS genes is to adopt a combined candidate gene and positional cloning approach and such efforts may be enhanced by a chance finding of a gross rearrangement. The correlation between PEI (1) and BBS in the patients in the present study may be coincidental and DNA linkage analysis is required to investigate a possible BBS gene locus on chromosome 1. Tommerup,16 although all the 22 cases of BBS of his study had normal karyotypes, reported how in several Mendalian disorders specific constitutional chromosome rearrangements have facilitated the localisation of the relevant locus. Familial translocations and inversions can predispose to the formation of uniparental disomy, whereby autosomal recessive mutations can be reduced to homozygosity.17
In conclusion, our observation of PEI (1) and review of published reports suggest that PEI carriers do not appear to be free of risks of abnormalities and caution is recommended when counselling. It also emphasises the importance of cytogenetic investigation in a familial Mendelian disorder to exclude possible chromosomal abnormalities and to understand the significance of familial inversions/variants or polymorphisms.
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