Mosaic microdeletion of 17p11.2–p12 and duplication of 17q22–q24 in a girl with Smith–Magenis phenotype and peripheral neuropathy

Goh, Elaine Suk‐Ying; Banwell, Brenda; Stavropoulos, Dimitri J.; Shago, Mary; Yoon, Grace

doi:10.1002/ajmg.a.36322

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…The mutations in RAI1 , located in the 17p11.2 locus are known to be responsible for the inversion of the melatonin cycle 24 . However, not all SMS patients with RAI1 mutations or deletions experience sleep disturbances 25 , hence the SMS phenotype may be achieved by complex rearrangements of chromosome 17 that also involve its long arm 26,27 . The observation of DNA methylation changes in the group of genes related to SMS requires further investigation, possibly in occupational cohorts of shift workers, since shift work can lead to circadian misalignments and sleep loss 5 .…”

Section: Discussionmentioning

confidence: 99%

A distinctive DNA methylation pattern in insufficient sleep

Lahtinen

Puttonen

Vanttola

et al. 2019

Sci Rep

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Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 ± 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 ± 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: “Nervous System Development” (FDR P value < 0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.

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Section: Discussionmentioning

confidence: 99%

A distinctive DNA methylation pattern in insufficient sleep

Lahtinen

Puttonen

Vanttola

et al. 2019

Sci Rep

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“…Her nerve conduction studies did not show any evidence of peripheral neuropathy. In contrast to BAB485, one mosaic case for the PMP22-RAI1 deletion reported by Goh et al (Goh et al 2014) did have facial features and developmental delays consistent with SMS, as well as hyporeflexia. NCS studies at the age of 7.5 years confirmed polyneuropathy.…”

Section: Resultsmentioning

confidence: 61%

“…Interestingly, there have been reports of rare large deletions that encompass both HNPP and SMS loci and include both PMP22 and RAI1 (Goh et al 2014; Juyal et al 1996; Liu et al 2011; Stankiewicz et al 2003; Trask et al 1996; Zori et al 1993). These deletions have breakpoints that are potentially beyond the regions defined by the LCR-mediated NAHR; thus, a different mechanism may be considered and investigated.…”

Section: Introductionmentioning

confidence: 99%

Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith–Magenis syndrome with evident peripheral neuropathy

Yuan

Neira

et al. 2016

Hum Genet

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Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e. PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e. PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.

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“…The haploinsufficiency of multiple contiguous genes usually results in neurodevelopmental disorders and variable degree of malformations. Differently from larger chromosomal imbalances and aneuploidies, mosaicism has been infrequently reported in microdeletion syndromes (Al‐Zahrani et al, 2011; Anderlid et al, 2014; Goh et al, 2014; Halder et al, 2018; Huynh et al, 2017; Messiaen et al, 2011; Shimada et al, 2014; Taylor et al, 2014; Tekin et al, 2000). Among the few mosaic microdeletion cases described, 22q11.2 microdeletion (Halder et al, 2018) and NF1 atypical microdeletion syndrome (Messiaen et al, 2011) are the most frequently reported.…”

Section: Discussionmentioning

confidence: 99%

Mosaic Williams syndrome: A case report

Kalantari

Biagio

Valente

et al. 2022

American J of Med Genetics Pt A

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Williams syndrome (WS) is a well‐known genetic disorder caused by heterozygous microdeletions of the 7q11.23 chromosome region. The main clinical features of the syndrome are characteristic facial dysmorphisms, cardiovascular and endocrine anomalies, short stature, mild‐to‐moderate intellectual disability, and a recognizable cognitive and behavioral profile. Differently from large chromosomal imbalances and aneuploidies, mosaicism has only rarely been found in microdeletion syndromes, and mosaic cases with WS phenotype have never been reported. We here describe a 51‐year‐old female patient with the typical clinical features of WS, whose chromosomal microarray analysis and fluorescence in situ hybridization disclosed a 54%–68% germline mosaicism for 7q11.23 deletion.

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Mosaic microdeletion of 17p11.2–p12 and duplication of 17q22–q24 in a girl with Smith–Magenis phenotype and peripheral neuropathy

Cited by 7 publications

References 19 publications

A distinctive DNA methylation pattern in insufficient sleep

A distinctive DNA methylation pattern in insufficient sleep

Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith–Magenis syndrome with evident peripheral neuropathy

Mosaic Williams syndrome: A case report

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