Unbalanced 14;X Translocation and Pattern of X Inactivation in a Female Patient with Multiple Congenital Anomalies.

We report on a female patient who was first evaluated at the age of 6 years with developmental delay, dysmorphic facial features, seizures, and autistic behavior. A brain CT showed complete agenesis of the corpus callosum, and EEG recorded bilateral epileptogenic foci. Karyotype analysis revealed 45,X,psu dic(14;X)(p11;p22). FISH using 14q and Xp subtelomeric probes, combined with a SHOX gene-specific probe, and centromere X and XIST gene analysis revealed ish psu dic(14;X)(D14S1420+; DXYS129-, SHOX-, DXZ1+, XIST+). Array CGH detected a 2-Mb loss at Xp22.33 and a 4.6-Mb gain at Xp22.2p22.12. The deletion contains 34 genes, of which CSF2RA and SHOX are OMIM morbid genes. The duplication also contains some OMIM morbid genes, of which CDKL5, NH5, RPS6KA3, and AP1S2 are the most important. The late replicating chromatin technique was used to detect the pattern of X inactivation in the normal X and in the translocated chromosome. The translocated X was found to be inactive in 70% of the studied blood lymphocytes with patchy extension of inactivation to chromosome 14. In conclusion, the phenotype of the patient may be partially affected by the haploinsufficiency of the genes that are known to escape X inactivation and that lie within the deleted region and by other deleted or duplicated genes on the abnormal X chromosome due to an alternative pattern of X inactivation. The phenotype of the patient was significantly aggravated and complicated by the functional monosomy of some genes on chromosome 14 due to partial spreading of inactivation and silencing of those genes. This case report indicates the importance of structural and functional studies and emphasizes the clinical importance of the follow-up of abnormal microarrays.

Intellectual disability secondary to a 16p13 duplication in a 1;16 translocation. Extended phenotype in a four-generation family.

We describe a large family from the Gaza Strip presented with multiple congenital anomalies. The proband was presented with intellectual disability and multiple congenital anomalies including cleft palate, low-set ears, everted upper lip, diaphragmatic hernia, and arthrogryposis. Pedigree analysis showed 19 affected patients over five generations, only 6 were alive and 11 individuals were obligate carriers. The proband had an apparently normal karyotype, although FISH studies showed a derivative chromosome 1 with duplication of 16p13.3 and deletion of the 1p subtelomere. Her father however had a balanced translocation. The seven affected patients had a similar phenotype, one of them died before genetic testing was carried out and the living six patients had the same unbalanced translocation. Array CGH revealed an 8.8 Mb duplication in 16p13 and 200,338 bp deletion in 1p36.3. Accordingly, intellectual disability, hypertelorism, cupped ears, everted upper lip, and limb anomalies were presenting clinical features of the 16p13 duplication syndrome while deep set eyes were perhaps related to the 1p terminal deletion. Prevention of recurrent intellectual disability in this family can be achieved through carrier detection and prenatal genetic diagnosis.