Two familial microduplications of 15q26.3 causing overgrowth and variable intellectual disability with normal copy number of IGF1R

Leffler, Melanie; Puusepp, Sanna; Žilina, Olga; Zhu, Ying; Kuuse, Kati; Bain, Nicole; Burgess, Trent; Õunap, Katrin; Field, Michael

doi:10.1016/j.ejmg.2015.12.002

Cited by 12 publications

(11 citation statements)

References 21 publications

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“…To our knowledge, only one case of a de novo chromosome 15q26.3 duplication has been reported to date ( 8 ). Two familial 15q26.3 duplications, respectively of 1.48 and 0.77 Mb, have recently been described ( 9 ). To understand the role that this specific breakpoint has in the clinical feature of the 15q overgrowth syndrome, we evaluated the IGF1R gene expression, the IGF1R biochemical activity, serum IGF1 levels and the clinical feature of Patients 1 and 2, respectively having a 568 kb pure and a 650 kb impure (Patient 2 had also a 600 16p11.2 kb deletion, this latter known as an autism susceptibility locus ( 10 )) chromosome 15q26.3 duplication.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

Cannarella

Mattina

Condorelli

et al. 2017

Endocrine Connections

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Insulin-like growth factor 1 receptor (IGF1R), mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the IGF1R gene expression and function in three unrelated patients with chromosome 15 structural abnormalities. We report two male patients with the smallest 15q26.3 chromosome duplication described so far, and a female patient with ring chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth, developmental delay, mental and psychomotor retardation, obesity, cryptorchidism, borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia. We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R protein expression (P < 0.05). Patient two, with a 650 kb impure duplication, showed overgrowth, developmental delay, mild mental retardation, precocious puberty, low testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and protein expression was similar to that of the control. Patient three, with a 46,XX r(15) (p10q26.2) karyotype, displayed intrauterine growth retardation, developmental delay, mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R mRNA expression and an undetectable IGF1R activity. After reviewing the previously 96 published cases of chromosome 15q duplication, we found that neurological disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are the prominent features in patients with chromosome 15q duplication. Interestingly, patients with 15q deletion syndrome display similar features. We speculate that both the increased and decreased IGF1R gene expression may play a role in the etiology of neurological and gonadal disorders.

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Section: Discussionmentioning

confidence: 99%

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

Cannarella

Mattina

Condorelli

et al. 2017

Endocrine Connections

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“…Although all the 17 likely pathogenic (LP) CNVs were not found in healthy individuals or in DGV ( http://dgv.tcag.ca/dgv/app/home ). They have been identified in more than one ID patients before ( Mégarbané et al, 2000 ; Rauch et al, 2003 ; Roggenbuck et al, 2004 ; Hellani et al, 2010 ; Dimitrov et al, 2011 ; Melis et al, 2012 ; Rush et al, 2013 ; Castillo et al, 2014 ; Balasubramanian et al, 2016 ; Leffler et al, 2016 ; Zhou et al, 2016 ; Akcakaya et al, 2017 ; Bonati et al, 2019 ; Holder-Espinasse et al, 2019 ; Allach El Khattabi et al, 2020 ). To determine the inheritance pattern, the parental DNA was available from the parent in 21 cases.…”

Section: Resultsmentioning

confidence: 99%

A Tiered Genetic Screening Strategy for the Molecular Diagnosis of Intellectual Disability in Chinese Patients

Dai

Zhang

et al. 2021

Front. Genet.

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Objective: Intellectual disability (ID) is one of the most common developmental disabilities. To identify the genetic etiology of IDs in Chongqing, we conducted a multistage study in Chinese Han patients.Methods: We collected the clinical and etiological data of 1665 ID patients, including 1,604 from the disabled children evaluation center and 61 from the pediatric rehabilitation unit. Routine genetic screening results were obtained, including karyotype and candidate gene analysis. Then 105 idiopathic cases with syndromic and severe ID/developmental delay (DD) were selected and tested by chromosomal microarray (CMA) and whole exome sequencing (WES) sequentially. The pathogenicity of the CNVs and SNVs were evaluated according to ACMG guidelines.Results: Molecular diagnosis was made by routine genetic screening in 216 patients, including 196 chromosomal syndromes. Among the 105 idiopathic patients, 49 patients with pathogenic/likely pathogenic CNVs and 21 patients with VUS were identified by CMA. Twenty-six pathogenic CNVs underlying well-known syndromic cases, such as Williams-Beuren syndrome, were confirmed by multiplex ligation-dependent probe amplification (MLPA). Nine novel mutations were identified by WES in thirty-fix CNV-negative ID cases.Conclusions: The study illustrated the genetic aberrations distribution of a large ID cohort in Chongqing. Compared with conventional or single methods, a tiered high-throughput diagnostic strategy was developed to greatly improve the diagnostic yields and extend the variation spectrum for idiopathic syndromic ID cases.

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“…Partial trisomy of the distal 15q is a rare chromosomal disorder. In general, the duplication of 15q has been characterized by prenatal and postnatal overgrowth, craniosynostosis, distinct facial features, and intellectual disability, likely reflecting triplosensitivity for one or more of the several genes that are found within this region [ 18 – 20 ]. The breakpoints and extent of the duplicated segment are variable among patients.…”

Section: Discussionmentioning

confidence: 99%

Genome wide noninvasive prenatal testing detects microduplication of the distal end of chromosome 15 in a fetus: a case report

et al. 2022

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Background Noninvasive prenatal testing (NIPT) is the most recent modality widely used in prenatal diagnostics. Commercially available NIPT has high sensitivity and specificity for the common fetal chromosomal aneuploidies. As future advancements in NIPT sequencing technology are becoming promising and more reliable, the ability to detect beyond aneuploidies and to expand detection of submicroscopic genomic alterations, as well as single-gene disorders might become possible. Case presentation Here we present a case of a 34-year-old pregnant woman, G2P1, who had NIPT screening which detected a terminal microduplication of 10.34 Mb on the long arm of chromosome 15 (15q26.1q26.3). Subsequent prenatal diagnostic testing including karyotype, microarray and fluorescence in situ hybridization (FISH) analyses were performed. Microarray testing confirmed and particularized a copy number gain of 10.66 Mb of the distal end of the long arm of chromosome 15. The G-banding cytogenetic studies yielded results consistent with unbalanced translocation between chromosome 15 and 18. To further characterize the abnormality involving the long arm of chromosome 18 and to map the genomic location of the duplicated 15q more precisely, FISH analysis using specific sub-telomeric probes was performed. FISH analysis confirmed that the extra duplicated segment of chromosome 15 is translocated onto the distal end of the long arm of chromosome 18 at band 18q23. Parental karyotype and FISH studies were performed to see if this unbalanced rearrangement was inherited from a healthy balanced translocation carrier versus being a de novo finding. Parental chromosomal analysis provided no evidence of a rearrangement between chromosome 15 and chromosome 18. The final fetal karyotype was reported as 46,XX,der(18)t(15;18)(q26.2;q23)dn. Conclusions In this case study, the microduplication of fetal chromosome 15q26.1q26.3 was accurately detected using NIPT. Our results suggest that further refinements in NIPT have the potential to evolve to a powerful and efficient screening method, which might be used to detect a broad range of chromosomal imbalances. Since microduplications and microdeletions are a potential reportable result with NIPT, this must be included in pre-test counseling. Prenatal diagnostic testing of such findings is strongly recommended.

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Two familial microduplications of 15q26.3 causing overgrowth and variable intellectual disability with normal copy number of IGF1R

Cited by 12 publications

References 21 publications

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

A Tiered Genetic Screening Strategy for the Molecular Diagnosis of Intellectual Disability in Chinese Patients

Genome wide noninvasive prenatal testing detects microduplication of the distal end of chromosome 15 in a fetus: a case report

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