An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3

Pebrel‐Richard, Céline; Debost‐Legrand, Anne; Eymard-Pierre, Éléonore; Grèze, Victoria; Kemeny, Stéphan; Gay‐Bellile, Mathilde; Gouas, Laëtitia; Tchirkov, Andréï; Vago, Philippe; Goumy, Carole; Francannet, Christine

doi:10.1038/ejhg.2013.141

Cited by 23 publications

(15 citation statements)

References 23 publications

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“…Low copy repeats at the 16p11.2 locus drive the formation of recurrent CNVs (Fig. 1) [5,[11][12][13][14][15] whose carriers experience increased risk for various neurodevelopmental disorders [3,[16][17][18][19][20][21][22][23][24][25] or somatic traits and diseases [17,[26][27][28][29][30]. Within the 16p11.2 region, the segment with breakpoints (BP) at 28.3 and 28.9 Mb (hg18, BP1-BP3) is referred to as the distal region.…”

Section: Introductionmentioning

confidence: 99%

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Sønderby¹,

Gústafsson²,

Doan³

et al. 2018

Mol Psychiatry

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Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10 −6 , 1.7 × 10 −9 , 3.5 × 10 −12 and 1.0 × 10 −4 , respectively). Full scale IQ was lower in both deletion and duplication carriers compared to noncarriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

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Section: Introductionmentioning

confidence: 99%

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Sønderby¹,

Gústafsson²,

Doan³

et al. 2018

Mol Psychiatry

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“…Deletion CNVs can unmask recessive coding or noncoding SNVs when inherited in trans (Figure C‐D) . Extensive investigations of CNV and SNV data at the 16p11.2 locus have shed light on various genetic models of penetrance at this locus, including mirror traits and involvement of noncoding and coding SNVs in trans with a deletion (Table ) . Extreme or atypical phenotypes in 22q11.2 deletion or DiGeorge syndrome [MIM 188400] have been attributed to SNVs in the remaining allele .…”

Section: Downstream Mechanisms: From Cnv To Phenotype and Beyondmentioning

confidence: 99%

Genomic disorders 20 years on—mechanisms for clinical manifestations

2017

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Genomic disorders result from copy-number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarrays, and more recently, whole genome sequencing and whole-exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent vs nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of noncoding CNVs to human disease.

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“…Similarly, 22q11.2 deletions associated with hemizygous variants in SNAP29 lead to cerebral dysgenesis, neuropathy, ichthyosis, palmoplantar, and keratoderma (CEDNIK) syndrome, while variants in the SCARF2 gene cause Van den Ende-Gupta syndrome [4,5]. Additional examples are the 16p11.2 and 16p13.11 regions in which variants in the CLN3 and NDE1 genes respectively result in unusually severe phenotypes [6,7]. It is worth noting that in these mentioned cases the recessive variant results in a null allele.…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance

et al. 2018

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Several hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes. This result demonstrates that the analysis of the genes included in non-deleted contralateral allele is a key point in the etiological investigation of patients harboring a deletion inherited from a parent. Finally, this strategy is also an interesting approach to identify new recessive intellectual disability genes.

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An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3

Cited by 23 publications

References 23 publications

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Genomic disorders 20 years on—mechanisms for clinical manifestations

Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance

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