Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1

Abstract

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder (incidence around 1 in 10 6 births), characterised by a complex immunologic defects, reduced pigmentation, and presence of giant granules in many different cell types. It most likely results from defective organellar trafficking or protein sorting. The causative gene (LYST) has recently been identified and shown to be homologous to the beige locus in the mouse. CHS has always been reported associated with premature-termination-codon mutations in both alleles of LYST. We report a unique patient with CHS, who was homozygous for a stop codon in the LYST gene on chromosome 1 and who had a normal 46,XY karyotype. The mother was found to be a carrier of the mutation, whereas the father had two normal LYST alleles. Non-paternity was excluded by the analysis of microsatellite markers from different chromosomes. The results of 13 informative microsatellite markers spanning the entire chromosome 1 revealed that the proband had a maternal isodisomy of chromosome 1 encompassing the LYST mutation. The proband's clinical presentation also confirms the absence of imprinted genes on chromosome 1.

CD45-deficient severe combined immunodeficiency caused by uniparental disomy

“…Although UPD has been implicated in the development of a number of inherited syndromes, it is not widely considered as an inheritance mechanism and has only been described in isolated cases of five other primary immune-deficiency syndromes, including C4 deficiency (22), cartilage-hair hypoplasia without associated SCID (23), Chediak-Higashi syndrome (24), familial hemophagocytic lymphohistiocytosis (25), and IFN-γ receptor 1 deficiency (26). Disease in our patient was because of isodisomy of Chr 1, and of the 23 other reported cases of this type of UPD (27), only one was associated with immune deficiency (24).…”

A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

“…Besides, a paternal meiotic involvement at the origin of these cases is also rather surprising, with 2n genotypes presumably arising from the correction of paternally induced trisomies 35,49 or from mitotic complementations of the monosomies resulting from a meiotic loss of the paternal member. 41,43 A survey of and a personal contribution to published maternal UPD7 cases 68 produced as many cases of heterodisomy after presumed maternal trisomy rescue (12) as cases of holo-isodisomy (11). In my view, although other mechanisms may be considered, the isodisomy group is best explained by maternal complementation of paternal gamete nullisomy.…”

Two cases of mosaic RhD blood-group phenotypes and paternal isodisomy for chromosome 1

“…They were found accidentally either through studies on rare autosomal recessive disorders, i.e., Herlitz junctional epidermolysis bullosa [Pulkkinen et al, 1997;Takizawa et al, 2000], pycnodysostosis [Gelb et al, 1998], Chediak-Higashi syndrome [Dufourcq-Lagelouse et al, 1999], congenital insensitivity to pain with anhidrosis [Miura et al, 2000], multiple congenital anomalies [Chen et al, 1999], or during a genome screening of families with insulin-dependent diabetes mellitus using polymorphic DNA markers [Field et al, 1998]. We would like to emphasize here that isodisomy 1 is not infrequent and also causes unusual Rh phenotypes.…”

“…UPD1 has been identi®ed in seven individuals [Pulkkinen et al, 1997;Field et al, 1998;Gelb et al, 1998;Dufourcq-Lagelouse et al, 1999;Chen et al, 1999;Miura et al, 2000;Takizawa et al, 2000]. They were found accidentally either through studies on rare autosomal recessive disorders, i.e., Herlitz junctional epidermolysis bullosa [Pulkkinen et al, 1997;Takizawa et al, 2000], pycnodysostosis [Gelb et al, 1998], Chediak-Higashi syndrome [Dufourcq-Lagelouse et al, 1999], congenital insensitivity to pain with anhidrosis [Miura et al, 2000], multiple congenital anomalies [Chen et al, 1999], or during a genome screening of families with insulin-dependent diabetes mellitus using polymorphic DNA markers [Field et al, 1998].…”

“…UPD in humans has been observed in all but chromosomes 3, 5, 12, 18, and 19 [Ledbetter and Engel, 1995;Benlian et al, 1996;Gelb et al, 1998]. There have been seven individuals reported with UPD for chromosome 1 (UPD1): those with maternal heterodisomy [Pulkkinen et al, 1997;Field et al, 1998], paternal heterodisomy [Gelb et al, 1998], maternal isodisomy [Dufourcq-Lagelouse et al, 1999], complete paternal isodisomy [Miura et al, 2000;Takizawa et al, 2000], and with paternal isodisomy for 1p/1q [Chen et al, 1999].…”