SNX8: A candidate gene for 7p22 cardiac malformations including tetralogy of fallot

Vanzo, Rena; Martin, Megan M.; Sdano, Mallory R.; Teta, Kathie; Aggarwal, Vimla S.; South, Sarah T.

doi:10.1002/ajmg.a.36242

Cited by 10 publications

(6 citation statements)

References 11 publications

(14 reference statements)

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“…Partial CNV deletions encompassing MAD1L are reported in case subjects with DD/ID and congenital abnormalities. 55 Despite recurrences in these subjects, these events were not observed within the 2,880 healthy individuals. Other identified regions that provided an area for exploration of disease etiology included epi-variants in candidate genes for ID (MTA1 [MIM: 603526]), 56 neurodevelopmental disorders (PTPRN2 [MIM: 601698]), 57 and neural developments and ID (PTPRO [MIM: 600579]), 58 as well as a hypermethylation event in an individual with seizures and ID in the ELFN1 (MIM: 614964) promoter (Figure 6D), a gene whose knock-out in mice induces seizures and ID.…”

Section: Exploration Of Rare Dna Methylation Epi-variants In Undiagnosed Individualsmentioning

confidence: 80%

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Aref‐Eshghi

Bend

Colaiacovo

et al. 2019

The American Journal of Human Genetics

141

151

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Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.

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Section: Exploration Of Rare Dna Methylation Epi-variants In Undiagnosed Individualsmentioning

confidence: 80%

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Aref‐Eshghi

Bend

Colaiacovo

et al. 2019

The American Journal of Human Genetics

141

151

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“…Since their report, there have been no further studies describing cardiac malformations associated with haploinsufficiency of MAD1L1, FTSJ2 , or NUDT1 . Haploinsufficiency of SNX8 has been reported in individuals both with and without cardiac anomalies and so currently, the evidence is conflicting (Rendu et al, ; Vanzo et al, ). This region is more terminally located than the region of overlap identified in our patients.…”

Section: Discussionmentioning

confidence: 99%

Variable developmental delays and characteristic facial features—A novel 7p22.3p22.2 microdeletion syndrome?

Zambrano

Cristian

et al. 2017

American J of Med Genetics Pt A

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Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.

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“…Overexpression of SNX8 suppresses the accumulation of fragments of amyloid precursor protein (Aβ). Additionally, patients lacking SNX8 were shown to have heart development defects, intellectual disability, learning and language delay, and severe behavioral problems related to the hyperactive-impulsive and inattentive area ( Vanzo et al, 2014 ; Rendu et al, 2014 ; Mastromoro et al, 2020 ). Although SNX8 has been linked to several diseases, its molecular function is still poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling

Suzuki

Oishi

Nikulin

et al. 2021

eLife

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Membrane protein recycling systems are essential for maintenance of the endosome-lysosome system. In yeast, retromer and Snx4 coat complexes are recruited to the endosomal surface where they recognize cargos. They sort cargo and deform the membrane into recycling tubules that bud from the endosome and target to the Golgi. Here, we reveal that the SNX-BAR protein, Mvp1, mediates an endosomal recycling pathway which is mechanistically distinct from the retromer and Snx4 pathways. Mvp1 deforms the endosomal membrane and sorts cargos containing a specific sorting motif into a membrane tubule. Subsequently, Mvp1 recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and release of the recycling tubule. Similarly, SNX8, the human homolog of Mvp1, which has been also implicated in Alzheimer's disease, mediates formation of an endosomal recycling tubule. Thus, we present evidence for a novel endosomal retrieval pathway that is conserved from yeast to humans.

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SNX8: A candidate gene for 7p22 cardiac malformations including tetralogy of fallot

Cited by 10 publications

References 11 publications

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Variable developmental delays and characteristic facial features—A novel 7p22.3p22.2 microdeletion syndrome?

A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling

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