Mental retardation and autism associated with recurrent 16p11.2 microdeletion: incomplete penetrance and variable expressivity

Čiuladaitė, Živilė; Kasnauskienė, Jüratė; Preikšaitienė, Eglė; Patsalis, Philippos C.; Kučinskas, Vaidutis

doi:10.1007/s13353-011-0063-z

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…Even though CNVs at 16p11.2 have been associated with epilepsy, this finding is not unexpected, as the phenotype of patients with these CNVs is extremely variable and the overlap between ASD and epilepsy is not often observed among them [55], [85]–[88].…”

Section: Discussionmentioning

confidence: 95%

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Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

et al. 2014

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Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.

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Section: Discussionmentioning

confidence: 95%

“…Indeed, it has been established that maternally and paternally inherited as well as de novo 16p11.2 microdeletions and microduplications contribute to the ASD phenotype [51], [53]–[55]. Additionally, 15q13.3 deletions and maternally inherited duplications at 15q11-q13 have been implicated in an increased risk of ASD [28], [56], [57].…”

Section: Discussionmentioning

confidence: 99%

Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

et al. 2014

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“…Estimates of the clinical penetrance of recurrent pathogenic copy number variants (CNVs) vary quite widely, depending upon CNV size, genomic location and the disorder in question (Ben-Shachar et al 2009; Vassos et al 2010; Breckpot et al 2011; Čiuladaitè et al 2011; Hosak et al 2012; Klopocki et al 2012; Rosenfeld et al 2013; Vaags et al 2012; Weischenfeldt et al 2013; Dabell et al 2013; Carvill and Mefford 2013; Tropeano et al 2013). In their study of children known to carry a CNV associated with intellectual disability and congenital abnormalities, Girirajan et al (2012) reported synergy between multiple large CNVs leading to a particularly severe clinical presentation.…”

Section: Influence Of Copy Number Variation On Mutation Penetrancementioning

confidence: 99%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

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“…16p11.2 deletions and duplications are additionally associated with speech delay, intellectual impairment, and developmental delays [Bassuk et al, ; Bijlsma et al, ; Cooper et al, ; Fernandez et al, ; Guilmatre et al, ; Hanson et al, ; Owen et al, ; Rosenfeld et al, ; Shinawi et al, ; Weiss et al, ; Zufferey et al, ], schizophrenia [Guilmatre et al, ; McCarthy et al, ; Rosenfeld et al, ; Steinberg et al, ; Szatkiewicz et al, ], bipolar disorder [Fernandez et al, ; McCarthy et al, ], depression [Degenhardt et al, ; Rosenfeld et al, ], and anxiety [Fernandez et al, ; Pinto et al, ; Rosenfeld et al, ]. Physiological abnormalities associated with 16p11.2 copy number variants are diverse, including motor hypotonia, seizures, feeding difficulty, obesity (deletion), low body weight (duplication), immune deficiency, syringomyelia, hearing loss, and cardiac defects [Bassuk et al, ; Bijlsma et al, ; Ciuladaite et al, ; Fernandez et al, ; Ghebranious, Giampietro, Wesbrook, & Rezkalla, ; Hanson et al, ; Jacquemont et al, ; Puvabanditsin et al, ; Rosenberg et al, ; Reinthaler et al ; Sanders et al, ; Schaaf et al, ; Shinawi et al, ; Shiow et al, ; Steinberg et al, ; Walters et al, ]. 16p11.2 deletions and duplications are not fully penetrant and some individuals are largely asymptomatic, though 16p11.2 deletions appear to be more deleterious than duplications [Bijlsma et al, ; Cooper et al, ; Fernandez et al, ; Glessner et al, ; Hanson et al, ; Kumar et al, ; Rosenfeld et al, ; Rosenfeld et al, ].…”

Section: Introductionmentioning

confidence: 99%

16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions

et al. 2015

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Recurrent deletions and duplications at chromosomal region 16p11.2 are variably associated with speech delay, autism spectrum disorder, developmental delay, schizophrenia, and cognitive impairments. Social communication deficits are a primary diagnostic symptom of autism. Here we investigated ultrasonic vocalizations (USVs) in young adult male 16p11.2 deletion mice during a novel three-phase male–female social interaction test that detects vocalizations emitted by a male in the presence of an estrous female, how the male changes its calling when the female is suddenly absent, and the extent to which calls resume when the female returns. Strikingly fewer vocalizations were detected in two independent cohorts of 16p11.2 heterozygous deletion males (+/−) during the first exposure to an unfamiliar estrous female, as compared to wildtype littermates (+/+). When the female was removed, +/+ emitted calls, but at a much lower level, whereas +/− males called minimally. Sensory and motor abnormalities were detected in +/−, including higher nociceptive thresholds, a complete absence of acoustic startle responses, and hearing loss in all +/− as confirmed by lack of auditory brainstem responses to frequencies between 8 and 100 kHz. Stereotyped circling and backflipping appeared in a small percentage of individuals, as previously reported. However, these sensory and motor phenotypes could not directly explain the low vocalizations in 16p11.2 deletion mice, since (a) +/− males displayed normal abilities to emit vocalizations when the female was subsequently reintroduced, and (b) +/− vocalized less than +/+ to social odor cues delivered on an inanimate cotton swab. Our findings support the concept that mouse USVs in social settings represent a response to social cues, and that 16p11.2 deletion mice are deficient in their initial USVs responses to novel social cues.

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Mental retardation and autism associated with recurrent 16p11.2 microdeletion: incomplete penetrance and variable expressivity

Cited by 15 publications

References 34 publications

Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions

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