We present three patients with variegated aneuploidy and premature centromere division (PCD), a rare chromosomal abnormality in humans. Comparison of these three and eight other patients with variegated aneuploidy related to PCD demonstrates a phenotype comprising most frequently microcephaly, CNS anomalies (with cerebellar affection and migration defects), mental retardation, pre-and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. The occurrence of Wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome or genome instability disorder with a high risk of malignancy. FISH studies in uncultured blood and buccal smear cells demonstrate that the random aneuploidies are not limited to cultured cells, but also occur in vivo.

Loss-of-function mutations of the MECP2 gene are the cause of most cases of Rett syndrome in females, a progressive neurodevelopmental disorder characterized by severe mental retardation, global regression, hand stereotypies, and microcephaly. On the other hand, gain of dosage of this gene causes the MECP2 duplication syndrome in males characterized by severe mental retardation, absence of speech development, infantile hypotonia, progressive spasticity, recurrent infections, and facial dysmorphism. Female carriers of a heterozygous duplication show a skewed X-inactivation pattern which is the most probable cause of the lack of clinical symptoms. In this paper, we describe a girl with a complex de novo copy number gain at Xq28 and non-skewed X-inactivation pattern that causes mental retardation and motor and language delay. This rearrangement implies triplication of the MECP2 and IRAK1 genes, but it does not span other proximal genes located in the common minimal region of patients affected by the MECP2 duplication syndrome. We conclude that the triplication leads to a severe phenotype due to random X-inactivation, while the preferential X chromosome inactivation in healthy carriers may be caused by a negative selection effect of the duplication on some proximal genes like ARD1A or HCFC1.

MECP2 duplication syndrome (MDS) is an X‐linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho‐motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation‐dependent probe amplification (MLPA). Using, a custom in‐house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype‐phenotype correlations, and thus more personalized genetic counselling.

No abstract

Fluorescent in-situ hybridization (FISH) of decondensed sperm nuclei has been used directly to evaluate the enrichment efficiency of human sperm separation using Sephadex gel filtration and human serum albumin (HSA) gradients. Control and processed spermatozoa were fixed and their nuclei decondensed. In-situ hybridization was carried out with a Y-specific DNA probe (DYZ1). Sephadex filtration yielded 52.5% Y-chromosome-bearing spermatozoa, HSA separation resulted in 49.4% Y-chromosome-bearing spermatozoa and in the untreated control sample the percentage of Y spermatozoa was 49.3%. Statistical analysis revealed no significant differences between the selection methods employed and the controls, and no real enrichment for X- or Y-bearing spermatozoa was detected for any of the selection methods assayed. The usefulness of the protocols reported for selection of spermatozoa by sex chromosome in couples at risk for X-linked diseases is discussed.

Diagnosis of homogeneous KS based on lymphocyte karyotyping should be contrasted in other tissues. Mucosa cells could help to better approximate the degree of germ cell mosaicism. Our results indicate that 47,XXY germ cells are not meiotically competent. Increased post-reductional aneuploidy rate is related to meiotic errors in 46,XY cells. Appropriate genetic counselling is recommended in KS.

Using fluorescent in-situ hybridization (FISH) we have evaluated, on a blind basis, the efficiency of flow cytometry to separate human X- and Y-chromosome bearing spermatozoa. Our data demonstrate that human spermatozoa can be sorted to a purity of 80-90% for X spermatozoa and of 60-70% for Y spermatozoa. Our results using triple FISH fully agree with the sorting treatment used in each case and corroborate the efficiency of the flow sorting technique for sperm sex selection. In these limited samples (200-500 sperm/donor), the frequencies of disomic or diploid spermatozoa were not increased when comparing the sorted samples with unselected samples or with our control series.

Background: Phylloid hypomelanosis is a rare neurocutaneous syndrome characterized by a pattern of hypopigmentation consisting of leaflike or oblong macules reminiscent of floral ornaments. Associated extracutaneous anomalies include cerebral, ocular, and skeletal defects. Recently it has been suggested that this phenotype originates from mosaic partial or complete trisomy 13. We report clinical and cytogenetic data for 2 cases. Observations: A bizarre pattern of multiple leaflike macules was noted in 2 girls with mental deficiency. In patient 1, additional anomalies included syndactyly, clinodactyly, trichomegaly of the eyelashes, low frontal hairline, and several pale pink telangiectatic macules. In patient 2, epileptic seizures, dental malposition, oligodontia, preauricular fistulas, scoliosis, tethered cord, and syringo-myelia were noted. A diagnosis of phylloid hypomelanosis was made in both patients. In both patients, blood lymphocytes showed a normal karyotype 46,XX; however, fibroblasts derived from lesional skin demonstrated tetrasomy of chromosome 13q21-qter in patient 1 and trisomy of 13q22-qter in patient 2. Conclusions: These 2 cases lend further support to the concept that phylloid hypomelanosis is a distinct clinicogenetic entity that should no longer be confused with pigmentary mosaicism of the Ito type. From a comparison of our cytogenetic findings with those documented in previous articles, we infer that phylloid hypomelanosis is most likely related to the 13q region.