Rare structural variants in the DOCK8 gene identified in a cohort of 439 patients with neurodevelopmental disorders

Krgovic, Danijela; Vokač, Nadja Kokalj; Zagorac, Andreja; Kumperščak, Hojka Gregorič

doi:10.1038/s41598-018-27824-0

Cited by 14 publications

(21 citation statements)

References 17 publications

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“…Also, we identified two sets of host genes, one previously associated with memory, cognition or other neurodevelopmental processes and the other set identified here as candidates for roles in cognition (Table S4). Examples of known human genes associated with memory also identified in our study include: NTM and KLHl20 that are associated with Alzheimer's disease and DOCK8 and KANK1 that are associated with neurodevelopmental disorders including memory potential [29][30][31]. Examples of known mouse genes associated with memory include Specc1 that was identified in a mouse genetic screen for avoidance learning [32], Prdx6 that was associated with neurogenesis and Alzheimer's disease in mice [33,34] and knock-out mice for Abl2, Nrg3, Shank2, Gria1, and Fgf14 that caused neurodevelopmental defects [35][36][37][38][39].…”

Section: Discussionmentioning

confidence: 72%

Genetic and metabolic links between the murine microbiome and memory

et al. 2020

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Background: Recent evidence has linked the gut microbiome to host behavior via the gut-brain axis [1-3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice. Results: A genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice. Conclusion: Together, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites.

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Section: Discussionmentioning

confidence: 72%

Genetic and metabolic links between the murine microbiome and memory

et al. 2020

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“…According to a specific woman’s consent to having CNV be reported, we did not communicate these results except for a de novo deletion in the chromosomal band 9p24.3 overlapping the OMIM gene DOCK8 . Recent reports describe, in carriers of DOCK8 deletions, variable clinical manifestations such as intellectual disability, developmental delay, facial dysmorphic features, autism spectrum disorders, and psychiatric behavior [17]. Additionally, duplications encompassing the DOCK8 gene are associated with anomalies in psychiatric behavior [18].…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Microarray Analysis versus Karyotyping in Fetuses with Increased Nuchal Translucency

et al. 2019

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We have carried out a retrospective study of chromosome anomalies associated with increased nuchal translucency (NT) in order to compare yield rates of karyotype, chromosome microarray analysis (CMA), and non-invasive prenatal testing (NIPT) in this condition. Presenting with increased NT or cystic hygroma ≥3.5 mm as an isolated sign, 249 fetuses underwent karyotype and/or CMA from 11 to 18 gestational weeks. Karyotype and fluorescence in situ hybridization (FISH) analyses detected 103 chromosomal anomalies including 95 aneuploidies and eight chromosomal rearrangements or derivatives. Further, seven pathogenic copy number variants (CNV), five likely pathogenic CNVs, and 15 variants of unknown significance (VOUS) were detected by CMA in fetuses with normal karyotype. Genetic testing is now facing new challenges due to results with uncertain clinical impacts. Additional investigations will be necessary to interpret these findings. More than 15% of the anomalies that we have diagnosed with invasive techniques could not be detected by NIPT. It is therefore definitely not recommended in the case of ultrasound anomalies. These results, while corroborating the use of CMA in fetuses with increased NT as a second tier after rapid aneuploidy testing, do not suggest a dismissal of karyotype analysis.

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“…Homozygous loss of function of the DOCK8 gene causes autosomal recessive hyper-IgE recurrent infection syndrome (Zhang et al, 2009). In addition, evidence was recently presented supporting a causal relationship between heterozygous disruption of DOCK8 and mental retardation, pervasive developmental disorders, autism, and bipolar disorders (Nava et al, 2013; Wang et al, 2016; Griggs et al, 2008; Glessner et al, 2017; Krgovic et al, 2018). Our results support the findings of Glessner et al (2017), who identified DOCK8/KANK1 as novel significant loci for ASD and ADHD.…”

Section: Discussionmentioning

confidence: 99%

MLPA is a practical and complementary alternative to CMA for diagnostic testing in patients with autism spectrum disorders and identifying new candidate CNVs associated with autism

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Capkova

et al. 2019

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BackgroundAutism spectrum disorder (ASD) is a complex heterogeneous developmental disease with a significant genetic background that is frequently caused by rare copy number variants (CNVs). Microarray-based whole-genome approaches for CNV detection are widely accepted. However, the clinical significance of most CNV is poorly understood, so results obtained using such methods are sometimes ambiguous. We therefore evaluated a targeted approach based on multiplex ligation-dependent probe amplification (MLPA) using selected probemixes to detect clinically relevant variants for diagnostic testing of ASD patients. We compare the reliability and efficiency of this test to those of chromosomal microarray analysis (CMA) and other tests available to our laboratory. In addition, we identify new candidate genes for ASD identified in a cohort of ASD-diagnosed patients.MethodWe describe the use of MLPA, CMA, and karyotyping to detect CNV in 92 ASD patients and evaluate their clinical significance.ResultPathogenic and likely pathogenic mutations were identified by CMA in eight (8.07% of the studied cohort) and 12 (13.04%) ASD patients, respectively, and in eight (8.07%) and four (4.35%) patients, respectively, by MLPA. The detected mutations include the 22q13.3 deletion, which was attributed to ring chromosome 22 formation based on karyotyping. CMA revealed a total of 91 rare CNV in 55 patients: eight pathogenic, 15 designated variants of unknown significance (VOUS)—likely pathogenic, 10 VOUS—uncertain, and 58 VOUS—likely benign or benign. MLPA revealed 18 CNV in 18 individuals: eight pathogenic, four designated as VOUS—likely pathogenic, and six designated as VOUS—likely benign/benign. Rare CNVs were detected in 17 (58.62%) out of 29 females and 38 (60.32%) out of 63 males in the cohort. Two genes, DOCK8 and PARK2, were found to be overlapped by CNV designated pathogenic, VOUS—likely pathogenic, or VOUS—uncertain in multiple patients. Moreover, the studied ASD cohort exhibited significant (p < 0.05) enrichment of duplications encompassing DOCK8.ConclusionMultiplex ligation-dependent probe amplification and CMA yielded concordant results for 12 patients bearing CNV designated pathogenic or VOUS—likely pathogenic. Unambiguous diagnoses were achieved for eight patients (corresponding to 8.7% of the total studied population) by both MLPA and CMA, for one (1.09%) patient by karyotyping, and for one (1.09%) patient by FRAXA testing. MLPA and CMA thus achieved identical reliability with respect to clinically relevant findings. As such, MLPA could be useful as a fast and inexpensive test in patients with syndromic autism. The detection rate of potentially pathogenic variants (VOUS—likely pathogenic) achieved by CMA was higher than that for MLPA (13.04% vs. 4.35%). However, there was no corresponding difference in the rate of unambiguous diagnoses of ASD patients. In addition, the results obtained suggest that DOCK8 may play a role in the etiology of ASD.

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Rare structural variants in the DOCK8 gene identified in a cohort of 439 patients with neurodevelopmental disorders

Cited by 14 publications

References 17 publications

Genetic and metabolic links between the murine microbiome and memory

Genetic and metabolic links between the murine microbiome and memory

Chromosomal Microarray Analysis versus Karyotyping in Fetuses with Increased Nuchal Translucency

MLPA is a practical and complementary alternative to CMA for diagnostic testing in patients with autism spectrum disorders and identifying new candidate CNVs associated with autism

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