Abstract:Submicroscopic duplications in the Miller-Dieker critical region have been recently described as new genomic disorders. To date, only a few cases have been reported with overlapping 17p13.3 duplications in this region. Also, small deletions that affect chromosome region 10p14→pter are rarely described in the literature. In this study, we describe, to our knowledge for the first time, a 5-year-old female patient with intellectual disability who has an unbalanced 10;17 translocation inherited from the father. Th… Show more
“…However, they have variably shown to date such clinical manifestations [ 9 ], and also our Patient 2, indeed, manifests only few of these features (hypotonia, motor delay, hypogammaglobulinaemia). Furthermore, in the present duplicated genomic fragment (spanning 15 Mb at 10p15.3-p13, from 136,145 to 15,415,339) is included GATA3 gene, whose defects (specifically its deletion) are associated to visual and auditory deficiencies [ 12 ], however not currently observed in the proband. Fig.…”
Introduction
In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified.
Patients’ presentation
We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations.
Conclusions
Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.
“…However, they have variably shown to date such clinical manifestations [ 9 ], and also our Patient 2, indeed, manifests only few of these features (hypotonia, motor delay, hypogammaglobulinaemia). Furthermore, in the present duplicated genomic fragment (spanning 15 Mb at 10p15.3-p13, from 136,145 to 15,415,339) is included GATA3 gene, whose defects (specifically its deletion) are associated to visual and auditory deficiencies [ 12 ], however not currently observed in the proband. Fig.…”
Introduction
In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified.
Patients’ presentation
We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations.
Conclusions
Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.
“…Cases 4 to 6 represent a brother, a sister and a maternal cousin from the same family. Four cases presented with visible G-bands by trypsin using Leishman (GTL) banding chromosomal abnormalities: three of them with subtelomeric abnormalities [case 18: 46,XY,der (6) ], in addition to the subtelomeric submicroscopic abnormalities. Four cases were diagnosed by aCGH and the others by MLPA/FISH.…”
Section: Resultsmentioning
confidence: 99%
“…2,5 Subtelomeric regions are gene-rich chromosomal regions with a highly repetitive structure, frequently involved in chromosomal rearrangements. 6,7 Cryptic subtelomeric abnormalities, syndromic or isolated, are well known causes of ID, and are responsible for 3% -16% of diagnoses.…”
Introduction: Intellectual disability affects 2% – 3% of the general population, with a chromosomal abnormality being found in 4% – 28% of these patients and a cryptic subtelomeric abnormality in 3% – 16%. In most cases, these subtelomeric rearrangements are submicroscopic, requiring techniques other than conventional karyotype for detection. They may be de novo or inherited from an affected parent or from a healthy carrier of a balanced chromosomal abnormality. The aim of this study was to characterize patients from our medical genetics center, in whom both a deletion and duplication in subtelomeric regions were found.Material and Methods: Clinical and cytogenetic characterization of 21 probands followed at our center, from 1998 until 2017, with subtelomeric rearrangements.Results: There were 21 probands from 19 families presenting with intellectual disability and facial dysmorphisms. Seven had behavior changes, five had epilepsy and 14 presented with some other sign or symptom. Four had chromosomal abnormalities detected by conventional karyotype and four were diagnosed by array-comparative genomic hybridization. In four cases, parental studies were not possible. The online mendelian inheritance in man classification was provided whenever any of the phenotypes (deletion or duplication syndrome) was dominant.Discussion: Patients and relevant family members were clinically and cytogenetically characterized. Although rare, subtelomeric changes are a substantial cause of syndromic intellectual disability with important familial repercussions. It is essential to remember that a normal array-comparative genomic hybridization result does not exclude a balanced rearrangement in the parents.Conclusion: Parental genetic studies are essential not only for a complete characterization of the rearrangement, but also for accurate genetic counselling and screening of family members at risk for recurrence.
“…It was hypothesized that the duplication of YWHAE might have an effect on neuronal network development and maturation, and was related to mild development delay and facial dysmorphisms while the duplication of PAFAH1B1 that lead to its overexpression, was associated with moderate to severe development delay and structural brain abnormalities [2,9]. Brain-imaging analysis was performed in seven of the eleven reported patients and only four showed structural brain abnormalities (Table 1), among which Corpus Callosum hypoplasia or agenesis represented the main brain abnormality [9,10,13,14]. Likewise, our patient presented corpus callosum hypoplasia.…”
Section: Discussionmentioning
confidence: 99%
“…So far, to the best of our knowledge, only 13 patients having large 17p13.3 duplications, including the entire MDS comprising both PAFAH1B1 and YWHAE genes have been reported [2,[9][10][11][12][13][14][15] (Fig. 6) with varying sizes and different breakpoints.…”
Background: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications. Methods: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed. Results: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3). Conclusions: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.
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