Clinical and molecular characterization of a boy with intellectual disability, facial dysmorphism, minor digital anomalies and a complex IL1RAPL1 intragenic rearrangement

Laino, Luigi; Bottillo, Irene; Piedimonte, Caterina; Bernardini, Laura; Torres, Bárbara; Grammatico, Barbara; Bargiacchi, Simone; Mulargia, Claudia; Calvani, Mauro; Cardona, Francesco; Castori, Marco; Grammatico, Paola

doi:10.1016/j.ejpn.2016.07.003

Cited by 8 publications

(3 citation statements)

References 33 publications

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“…This is consistent with the family reported herein, in which the 2 females bearing the large CNV in the X chromosome (I.1 and II.1) had a complete skewed X-chromosome inactivation, whereas patient II.3, bearing only the small intragenic IL1RAPL1 CNV, had random X inactivation. This has also been recently reported in another family with intragenic IL1RAPL1 duplication [Laino et al, 2016].…”

Section: Discussionmentioning

confidence: 55%

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

et al. 2017

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We report a 3-generation family in which 2 Xp copy number variations (CNVs) co-segregate. The proband presented with syndromic intellectual disability. The CNV had been revealed by conventional karyotyping, identifying a large Xp22 duplication causing an Xp functional disomy. Family studies found that this duplication was inherited from the proband's mother and was also present in one of his sisters. This sister had conventional karyotyping performed during pregnancy with a normal result. Postnatally, her child, the proband's nephew, presented with autism spectrum disorders. aCGH revealed a 339-kb IL1RAPL1 duplication. Overall, the proband, his mother, and one of his sisters all harboured both CNVs, while his other sister and the 2 sons of each sister only carried the IL1RAPL1 intragenic duplication. As seen in this family, we emphasise the importance of small CNV detection, the pathogenicity of IL1RAPL1 exonic duplications in male carriers, and the difficulties for genetic counselling with the risk of double diagnosis in a single patient.

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Section: Discussionmentioning

confidence: 55%

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

et al. 2017

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“…Via a literature search, we retrieved 13 intragenic CNVs in IL1RAPL1 from 10 studies (Chatron et al, 2017;Honda et al, 2010;Laino et al, 2016;Mignon-Ravix et al, 2014;Mikhail et al, 2011;Ramos-Brossier et al, 2015;Roberts et al, 2014;Whibley et al, 2010;Whitehead et al, 2016;Zarrei et al, 2019), including 6 variants, 3 deletions, and 3 duplications, covering exon 6 (Laino et al, 2016;Ramos-Brossier et al, 2015;Roberts et al, 2014;Whitehead et al, 2016). This showed that no recurrent variants were found intragenically.…”

Section: Family Fin41 Shows a Non-continuous Microduplication At Xp212 Covering Exon 6 Of Il1rapl1mentioning

confidence: 99%

Identification of microduplications at Xp21.2 and Xq13.1 in neurodevelopmental disorders

Kokkonen

Siren

Määttä

et al. 2021

Molec Gen & Gen Med

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Background: Microduplications are a rare cause of disease in X-linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation. Methods: We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder. Results: Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8-kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223-and 204-kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re-arrangement. Conclusion:In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X-chromosome can be helpful in undiagnosed cases of neurodevelopmental disease.

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“…According to the UCSC genome browser, these segments are considered to be derived from repeating elements overlapped with LINE (L1MB7; Figure S10). Previous studies have reported chromosomal abnormalities disrupting the IL1RAPL1 region (Barone et al, 2013;Bhat et al, 2008;Chatron et al, 2017;Franek et al, 2011;Laino et al, 2016;Moyses-Oliveira et al, 2015;Youngs, Henkhaus, Hellings, & Butler, 2012). Therefore, this region may be fragile and prone to chromosomal abnormalities.…”

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confidence: 99%

Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern

et al. 2020

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Chromosomal triplications can be classified into recurrent and nonrecurrent triplications. Most of the nonrecurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern.

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Clinical and molecular characterization of a boy with intellectual disability, facial dysmorphism, minor digital anomalies and a complex IL1RAPL1 intragenic rearrangement

Cited by 8 publications

References 33 publications

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

Identification of microduplications at Xp21.2 and Xq13.1 in neurodevelopmental disorders

Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern

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