Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations

Abstract

We report array-CGH screening of 95 syndromic patients with normal G-banded karyotypes and at least one of the following features: mental retardation, heart defects, deafness, obesity, craniofacial dysmorphisms or urogenital tract malformations. Chromosome imbalances not previously detected in normal controls were found in 30 patients (31%) and at least 16 of them (17%) seem to be causally related to the abnormal phenotypes. Eight of the causative imbalances had not been described previously and pointed to new chromosome regions and candidate genes for specific phenotypes, including a connective tissue disease locus on 2p16.3, another for obesity on 7q22.1→q22.3, and a candidate gene for the 3q29 deletion syndrome manifestations. The other causative alterations had already been associated with well-defined phenotypes including Sotos syndrome, and the 1p36 and 22q11.21 microdeletion syndromes. However, the clinical features of these latter patients were either not typical or specific enough to allow diagnosis before detection of chromosome imbalances. For instance, three patients with overlapping deletions in 22q11.21 were ascertained through entirely different clinical features, i.e., heart defect, utero-vaginal aplasia, and mental retardation associated with psychotic disease. Our results demonstrate that ascertainment through whole-genome screening of syndromic patients by array-CGH leads not only to the description of new syndromes, but also to the recognition of a broader spectrum of features for already described syndromes. Furthermore, on the technical side, we have significantly reduced the amount of reagents used and costs involved in the array-CGH protocol, without evident reduction in efficiency, bringing the method more within reach of centers with limited budgets.

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

“…Although the selection criteria for array-CGH investigations are highly variable, similar reports in the Brazilian population showed approximately the same detection rate of pathological CNVs. Among 95 Brazilian syndromic patients, Krepischi-Santos et al (2006) accounted for 17% of CNVs to be causally related to abnormal phenotypes. Pereira et al (2014) detected 22% of pathogenic CNVs in 15 patients from Central Brazil who had IDs.…”

“…In Brazilian studies, genome changes investigated by array techniques have been detected in up to 25% of patients with idiopathic syndromic ID (Krepischi-Santos et al, 2006;Hochstenbach et al, 2011).…”

Mini-Review Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes

“…Among these, 17 scientific articles met the criteria for inclusion and were selected for this study (D'Angelo et al, 2006;Krepischi-Santos et al, 2006;Kang et al, 2007;Robinson et al, 2008;Bursztejn et al, 2009;El-Hattab et al, 2010;Gajecka et al, 2010;Rosenfeld et al, 2010;Haimi et al, 2011;Mikhail et al, 2011;Nicoulaz et al, 2011;Giannikou et al, 2012;Gervasini et al, 2013;Shiba et al, 2013;Zhu et al, 2013;Shimada et al, 2014;Stagi et al, 2014). Among these, 12 were case reports and five reported series of cases.…”

Microarreglos cromosómicos en 236 pacientes chilenos con trastornos del neurodesarrollo y anomalías congénitas

“…Se destaca en este trabajo el tamaño de la muestra, que sería la más grande reportada en Sudamérica 12,17,18 y que se incluyeron pacientes provenientes de todo Chile, lo que contribuye, con mayor precisión, a conocer la prevalencia de este tipo de alteraciones genéticas en la población chilena. Por otro lado, es importante destacar que la asociación de un diagnóstico positivo por CMA con factores como el sexo del paciente, edad y el tipo de diagnóstico no habían sido descritos antes en población chilena.…”

“…Tanto los TN como las AC se manifiestan en la infancia, lo que amerita su derivación en esta etapa de la vida 1,2 . La tasa de diagnóstico de 19% estimada en el presente estudio podría ser considerada como la prevalencia de estos desbalances en población chilena con TN, AC o ambos, lo que concuerda además con las cifras promedio reportadas internacionalmente (entre 15 a 20%) 11,17,18 . Sin embargo, esta podría ser mayor, ya que en el estudio previo realizado en Chile 12 se detectó variantes clínicamente significativas en 25% de los pacientes, porcentaje que sube a cerca de 29%, si se consideran solo aquellos pacientes con cariotipo convencional normal.…”