9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression

Bonati, Maria Teresa; Castronovo, Chiara; Sironi, Alessandra; Zimbalatti, Dario; Bestetti, Ilaria; Crippa, Milena; Novelli, Antonio; Loddo, Sara; Dentici, Maria Lisa; Taylor, Juliet; Devillard, Françoise; Larizza, Lidia; Finelli, Palma

doi:10.1007/s10048-019-00581-6

Cited by 14 publications

(14 citation statements)

References 43 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further functional studies will be needed to confirm our findings. Here we provide a first evidence that digenic inheritance may be an alternative mechanism involved in the etiopathogenesis of NS and RASopathies, as already hypothesized [ 7 , 33 ]. Moreover, we have identified two novel genes, LRP1 and RASAL3 , possibly involved in the etiopathogenesis of NS/RASopathies.…”

Section: Discussionsupporting

confidence: 70%

Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?

et al. 2020

Self Cite

View full text Add to dashboard Cite

Noonan syndrome (NS) is an autosomal-dominant disorder with variable expressivity and locus heterogeneity. Despite several RAS pathway genes were implicated in NS, 20–30% of patients remain without molecular diagnosis, suggesting the involvement of further genes or multiple mechanisms. Eight patients out of 60, negative for conventional NS mutation analysis, with heterogeneous NS phenotype were investigated by means of target resequencing of 26 RAS/MAPK pathway genes. A trio was further characterized by means of whole-exome sequencing. Protein modeling and in silico prediction of protein stability allowed to identify possible pathogenic RAS pathway variants in four NS patients. A new c.355T>C variant in LZTR1 was found in patient 43. Two patients co-inherited variants in LRP1 and LZTR1 (patient 53), or LRP1 and SOS1 genes (patient 67). The forth patient (56) carried a compound heterozygote of RASAL3 gene variants and also an A2ML1 variant. While these subclinical variants are singularly present in healthy parents, they co-segregate in patients, suggesting their addictive effect and supporting a digenic inheritance, as alternative model to a more common monogenic transmission. The ERK1/2 and SAPK/JNK activation state, assessed on immortalized lymphocytes from patients 53 and 67 showed highest phosphorylation levels compared to their asymptomatic parents. These findings together with the lack of their co-occurrence in the 1000Genomes database strengthen the hypothesis of digenic inheritance in a subset of NS patients. This study suggests caution in the exclusion of subclinical variants that might play a pathogenic role providing new insights for alternative hereditary mechanisms.

show abstract

Section: Discussionsupporting

confidence: 70%

Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.

View full text Add to dashboard Cite

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.

show abstract

“…Although sharing deleted genes, the 21 different microdeletions analyzed do not appear to share common breakpoints, a finding which may account for non recurrent microdeletions at the population level [ 30 , 31 ]. The different rearrangement sizes, genomic extents, and breakpoint positions suggest non-homologous end joining (NHEJ) and replication mechanisms as the main causative drivers of the described microdeletions [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

Catusi

Garzo

Capra

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

show abstract

9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression

Cited by 14 publications

References 43 publications

Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?

Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?

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

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

Contact Info

Product

Resources

About