Does chromosome 22 have anything to do with sex determination: Further studies on a 46,XX,22q11.2 del male

Abstract

Several years ago, we presented a patient with true hermaphroditism and partial duplication of chromosome 22 and no evidence of SRY (Aleck et al. [1999: Am J Med Genet 85:2-4]). Recently a 46,XX male with velocardiofacial syndrome and a deletion of 22q11.2 and no evidence of Y chromosomal loci in blood DNA was reported (Phelan et al. [2003: Am J Med Genet 116A:77-79]). We have restudied this patient as he enters puberty. Because chromosomal deletions sometimes involve micro rearrangements of nearby material, we have extensively studied this individual's chromosome 22 looking for evidence of any gene duplication. We studied a number of variable number tandem repeat (VNTR) loci along chromosome 22 in the patient and both parents. Normal Mendelian inheritance of the VNTRs was found. We then used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to delineate the 22q11.2 deletion in this patient (Jacquet et al. [2002: Hum Molec Genet 11:2243-2249]) and found a pattern of deletion typical of the velocardiofacial DiGeorge syndrome. Finally, the patient's DNA has been analyzed using a full coverage human chromosome 22 genomic microarray (array comparative genomic hybridization [CGH]) for evidence of rearrangements outside the classical velocardiofacial DiGeorge associated deletion (Buckley et al. [2002: Hum Molec Genet 11:3221-3229]). The array-CGH profile of this patient confirms the deletion encompassing the typically deleted region associated with the velocardiofacial DiGeorge syndrome and provides no support for additional gene copy number aberrations on 22q. Thus, there is no evidence of any chromosome 22 trisomic material. In this case, the rare events of sex reversal and 22q11.2 deletion may have occurred together by chance.

22q11.2q13 duplication including SOX10 causes sex‐reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease

“…In 2003, the same group reported on another patient with an XX male phenotype and a typical 22q11.2 deletion. The authors concluded that the deletion and sex reversal phenotypes may have co‐occurred in the same individual by chance, given the high frequency of the typical 22q11.2 deletion (Erickson et al, ). Polanco et al () using a transgenic mouse approach, tested the hypothesis that Sox10 overexpression causes XX sex reversal, proposing that human SOX10 is involved in 22q duplication 46,XX male syndrome.…”

9p partial monosomy and disorders of sex development: Review and postulation of a pathogenetic mechanism

“…This deletion may provide a partial explanation of the VSD in Patient 2 with haploinsufficiency for CRKL (within the deleted segment) suggested as a candidate gene responsible for the CHD in these patients [Breckpot et al, ]. 46,XY gonadal dysgenesis has not been reported in these patients, but two patients have been reported with 46,XX testicular DSD who were found to have the DiGeorge deletion [Phelan et al, ; Erickson et al, ]. Similar to the presence of the 45,X cell line, this deletion makes assigning responsibility to any one causative cytogenetic aberration difficult.…”

Mammalian sex determination—insights from humans and mice

“…The gene responsible for this DSD phenotype is still unknown, but EMX2 has been suggested to be a likely candidate (Ogata et al 2000). Deletions and duplications of chromosome 22q11.2 have been identified in three cases of 46,XX testicular DSD (which were SRY -negative) (Aleck et al 1999; Erickson et al 2003; Seeherunvong et al 2004). The causative gene(s) haven't been identified, but this region contains the MAPK1 gene, which appears to play an important role in proper testis development.…”