Twenty-one patients, including our two cases, with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or overlapping features with DiGeorge/velocardiofacial syndromes (DG/VCFS), have been shown to have a chromosome duplication 22q11 of the region that is deleted in patients with DG/VCFS. The reported cases have been identified primarily by interphase FISH and could have escaped identification and been missed by routine cytogenetic analysis. Here we report on two inherited cases, referred to us, to rule out 22q11 microdeletion diagnosis of VCFS. The first patient was a 2-month-old girl, who presented with cleft palate, minor dysmorphic features including short palpebral fissures, widely spaced eyes, long fingers, and hearing loss. Her affected mother had mild mental retardation and learning disabilities. The second patient was a 7(1/2)-year-old boy with velopharyngeal insufficiency and mild developmental delay. He had a left preauricular tag, bifida uvula, bilateral fifth finger clinodactyly, and bilateral cryptorchidism. His facial features appeared mildly dysmorphic with hypertelorism, large nose, and micro/retrognathia. The affected father had mild mental retardation and had similar facial features. FISH analysis of interphase cells showed three TUPLE1-probe signals with two chromosome-specific identification probes in each cell. FISH analysis did not show the duplication on the initial testing of metaphase chromosomes. On review, band q11.2 was brighter on one chromosome 22 in some metaphase spreads. The paucity of reported cases of 22q11.2 microduplication likely reflects a combination of phenotypic diversity and the difficulty of diagnosis by FISH analysis on metaphase spreads. These findings illustrate the importance of scanning interphase nuclei when performing FISH analysis for any of the genomic disorders.
We describe a female infant with severe abnormal phenotype with a de novo partial duplication of the short arm of the X chromosome. Chromosome painting confirmed the origin of this X duplication. Molecular cytogenetic analysis with fluorescence in situ hybridization (FISH) was performed with YAC probes, further delineating the breakpoints. The karyotype was 46, X dup(X)(p11-p21.2). Cytogenetic replication studies showed that the normal and duplicated X chromosomes were randomly inactivated in lymphocytes. In most females with structurally abnormal X chromosomes, the abnormal chromosome is inactivated and they are phenotypically apparently normal relatives of phenotypically abnormal males having dupX. Therefore, in this case, there is functional disomy of Xp11-p21.2 in the cells with an active dup(X), most likely resulting in abnormal clinical findings in the patient.
Translocations involving the short arms of the X and Y in human chromosomes are uncommon. One of the best-known consequences of such exchanges is sex reversal in 46,XX males and some 46,XY females, due to exchange in the paternal germline of terminal portions of Xp and Yp, including the SRY gene. Translocations of Xp segments to the Y chromosome result in functional disomy of the X chromosome with an abnormal phenotype and sex reversal if the DSS locus, mapped in Xp21, is present. We describe a 7-month-old girl with severe psychomotor retardation, minor anomalies, malformations, and female external genitalia. Cytogenetic analysis showed a 46,X,mar karyotype. The marker was identified as a der(Y)t(Xp;Yp) by fluorescence in situ hybridisation analysis. Further studies with specific locus probes of X and Y chromosomes made it possible to clarify the break points and demonstrated the presence of two copies of the DAX1 gene, one on the normal X chromosome and one on the der(Y). The karyotype of the child was: 46,X,der(Y)t(X;Y)(p21.2;p11.3). The syndrome resulted from functional disomy Xp21.2-pter, with sex reversal related to the presence of two active copies of the DAX1 gene located in Xp21. Few cases of Xp disomy with sex reversal have been reported, primarily related to Xp duplications with 46,XY karyotype, and less often to Xp;Yq translocations. To our knowledge, our patient with sex reversal and a t(Xp;Yp) is the second reported case.
A pericentric inversion of chromosome 9 has been detected in 10 unrelated families. The break points are identical and the inversions involved the heterochromatic segment. The effects of inversion of chromosome 9 on different aspects of reproductive failure are discussed.
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