NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families

Shehhi, Maryam Al; Forman, Eva; Fitzgerald, Jacqueline; McInerney, Veronica; Krawczyk, Janusz; Shen, Sanbing; Betts, David R.; Ardle, Linda Mc; Gorman, Kathleen; King, Mary D.; Green, Andrew J.; Gallagher, Louise; Lynch, Sally Ann

doi:10.1016/j.ejmg.2018.07.015

Cited by 57 publications

(60 citation statements)

References 18 publications

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“…In clinically ascertained populations, moderate-to-severe ID represents the clinical phenotype most frequently associated with NRXN1 exonic deletions (77%-92%). 13,17,24 Other commonly co-occurring behavioral conditions include ASD (43%-70%), 13,17,24,72,73 ADHD (9%-41%), 12,24 anxiety (6-7%) 12,13 and schizophrenia (5%). 12 Among neurological phenotypes, epilepsy has been reported in 14% to 53% of NRXN1 deletion carriers 13,17,24,72 and muscle hypotonia in 38% to 47%.…”

Section: Phenotypic Spectrum Of Heterozygous Nrxn1 Exonic Deletionsmentioning

confidence: 99%

Phenotypic spectrum of NRXN1 mono‐ and bi‐allelic deficiency: A systematic review

Castronovo¹,

Baccarin²,

Ricciardello

et al. 2019

Clinical Genetics

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Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with monoallelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions. K E Y W O R D S autism spectrum disorder, compound heterozygosity, developmental delay, neurexin 1, Pitt-Hopkins-like syndrome 2, schizophrenia

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Section: Phenotypic Spectrum Of Heterozygous Nrxn1 Exonic Deletionsmentioning

confidence: 99%

Phenotypic spectrum of NRXN1 mono‐ and bi‐allelic deficiency: A systematic review

Castronovo¹,

Baccarin²,

Ricciardello

et al. 2019

Clinical Genetics

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“…To validate this finding, we examined 76 published case reports of affected individuals with pathogenic variants in a subset of 22 autism genes that appeared in all three autism gene databases ( Table 1, Table S2 ). For example, recent case studies have identified autism cooccurring with ID in 21 individuals with de novo SHANK3 variants 15 , 19 individuals with NRXN1 variants 16 , and 18 individuals with TCF20 variants 17 . Overall, 460/497 (92.6%) individuals with autism described in these studies had ID features, emphasizing that variants in these genes contribute to a severe form of autism with comorbid ID (Table 1) .…”

mentioning

confidence: 99%

Gene discoveries in autism are biased towards comorbidity with intellectual disability

Jensen

Smolen

Girirajan

2019

Preprint

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21Autism typically presents with a highly heterogeneous set of features, including frequent 22we found that individuals with de novo LGD variants (IQ=77.7, p=0.031, Whitney test) or pathogenic CNVs (IQ=76.3, p=0.002) had a significant decrease in IQ scores 65 compared with individuals without such variants (IQ=82.3) ( Figure 1A). However, no 66 differences in autism severity, measured using SRS T-scores, were observed between groups of 67 individuals with and without pathogenic variants (p=0.104 for LGD variants and 0.963 for 68 CNVs) ( Figure 1A). This suggests that pathogenic variants in general contribute to ID 69 independent of autism severity, although this could also be due to an ascertainment bias in the 70 SSC cohort towards individuals with severe autism. 71We further identified individuals carrying de novo LGD variants in 173 autism-associated 72 genes, defined as genes with recurrent de novo variants reported in multiple databases of 73 manifesting ID among individuals with autism (p=0.035, 95% confidence interval 1.03-2.26), 96 and pathogenic CNVs similarly conferred a 1.92-fold increased risk for co-occurrence of ID 97 among individuals with autism (p=0.099, 95% CI 0.88-4.18). We replicated these observations 98 by analyzing an additional combined cohort of 2,357 individuals from both the SSC and the 99 Autism Sequencing Collection 18 . Here, individuals with autism and ID had a significantly higher 100 rate (p=3.04×10 -6 , one-tailed Student's t-test) of de novo variants in genes intolerant to variation, 101as measured by probability of Loss-of-function Intolerant (pLI) score >0.9 (70/643, 10.8%), than 102 individuals manifesting autism but not ID (114/1747, 6.65%). We also found that only 3/397 BrainSpan Atlas 21 , using the Specific-Expression Analysis (SEA) online tool 22 . While autism 126 genes were enriched for specific expression in the cortex (p=3.13×10 -4 , Fisher's Exact test with 127Benjamini-Hochsberg correction) and cerebellum (p=0.020) during early fetal development 22 , 128 genes with de novo LGD variants in high-functioning autism individuals were not enriched for 129 any specific expression patterns in the developing brain (Figure 2B). Furthermore, mouse 130 models of genes identified in individuals with high-functioning autism, whose phenotypic data 131 were obtained from the Mouse Genome Informatics database 24 , were significantly less likely to 132 manifest nervous system (p=4.90×10 -3 , one-tailed Fisher's Exact test with Benjamini-Hochsberg 133 correction) and behavioral/neurological (p=0.037) phenotypes than mouse models of reported 223 224 5. Fischbach, G.D., and Lord, C. (2010). The Simons Simplex Collection: A Resource for 225

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“…NRXN-family of genes, STXBP1, and SYT1 in CASK mutation carriers provide a phenotypic link to other NDD genes. For instance, NRXN1 is one of the most studied NDD genes in which homozygous mutations cause Pitt-Hopkins-Like syndrome 2 characterized by NDDs such as ID and ASD (Zweier et al, 2009) and heterozygous deletions predispose to several NDDs, psychiatric disorders as well as congenital malformations (Al Shehhi et al, 2019;Dabell et al, 2013). Mutations in STXBP1 were first described in patients with early infantile epileptic encephalopathy and are a common cause of epilepsy and encephalopathy with ID (Saitsu et al, 2008;Stamberger et al, 2016;Uddin et al, 2017).…”

Section: Cask-related Disorders Have Emerged As An Important Genetic mentioning

confidence: 99%

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

Becker

Mastropasqua

Reising

et al. 2019

Preprint

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HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels Summary (150 words)CASK-related disorders are a genetically defined group of neurodevelopmental syndromes.There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASKdeficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

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NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families

Cited by 57 publications

References 18 publications

Phenotypic spectrum of NRXN1 mono‐ and bi‐allelic deficiency: A systematic review

Phenotypic spectrum of NRXN1 mono‐ and bi‐allelic deficiency: A systematic review

Gene discoveries in autism are biased towards comorbidity with intellectual disability

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

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