Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum.

Pancytopenia, hyperpigmentation, small stature, congenital abnormalities, and predisposition to neoplasia characterize Fanconi anemia (FA). The clinical phenotype is extremely variable, therefore the diagnosis is frequently delayed until the pancytopenia appears, making diagnosis difficult on the basis of clinical manifestations alone. Hypersensitivity of FA cells to the clastogenic effect of diepoxybutane (DEB) provides a unique marker for the diagnosis before the beginning of hematological manifestations. Our aim in this study was to detect FA in children with atypical manifestations to define which conditions should be routinely included in the DEB test screening. We performed the chromosomal breakage test in 34 patients with probable FA and 83 patients with clinical conditions that could suggest FA, but are not usually screened by the DEB test: 20 patients with aplastic anemia, 20 patients with VACTERL association, 20 with radial ray abnormalities, 7 with tracheo-esophageal fistulae, 12 with anal atresia, and 4 with myelodysplastic syndrome. We found 18 DEBpositive patients: 12 were in the group of probable FA and 6 in the other groups. Among the last ones: three were included because of aplastic anemia, without any other sign of FA, however when re-examined, other anomalies were detected. The third patient had anal atresia, renal hypoplasia, pre-axial polydactyly, and normal blood cell counts and was diagnosed as having VAC-TERL association. The other two patients lacking physical or hematological signs were identified among the group of radial ray abnormalities. Thus, our results highlight the need to increase the number of abnormalities indicating need for a DEB test. Delay in the diagnosis of FA may have serious consequences for the patients and their family members. ß

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Children with genetic diseases must be followed for long periods of time to seek new findings. Other patients require further check-ups and studies to be diagnosed. Some patients never return for medical care after the first consultation, which may have serious consequences. We reviewed 400 medical charts of patients with genetic disease to analyze overall attendance to the genetics clinic, investigate some of the causes of failure to seek medical advice, and determine the differences between those first seen as outpatients or as inpatients. The mean follow-up period was 8.3 months (range 0-79), and the average number of visits was 2.8 (range 1-16). Forty eight percent of the cases first seen as inpatients were evaluated only once and 14% twice; while 22 and 21% of the 300 cases first seen as outpatients attended once and twice, respectively (P = 0.0). Appointment keeping was apparently not affected by the presence or absence of diagnosis. Overall, 97 patients were discharged, 7 died, 55 continued on follow-up, 62 attended other hospital services-but not genetics-and 179 were completely lost to follow-up. Diagnosed patients were counseled more frequently than undiagnosed patients (62 vs. 5%); and 71% of the diagnosed patients first seen as outpatients but only 36% of undiagnosed cases first seen as inpatients were counseled, differences between these two groups were significant (P = 0.005). We conclude that keeping the patient with genetic disease on follow-up is a difficult task. New educational strategies must be planned to improve this worrisome situation.