A genome-wide association study reveals a polygenic architecture of speech-in-noise deficits in individuals with self-reported normal hearing.

Speech-in-noise (SIN) perception is a primary complaint of individuals with audiometric hearing loss. SIN performance varies drastically, even among individuals with normal hearing. The present genome-wide association study (GWAS) investigated the genetic basis of SIN deficits in individuals with self-reported normal hearing in quiet situations. GWAS was performed on 279,911 individuals from the UB Biobank cohort, with 58,847 reporting SIN deficits despite reporting normal hearing in quiet. GWAS identified 996 single nucleotide polymorphisms (SNPs), achieving significance (p < 5*10-8) across four genomic loci. 720 SNPs across 21 loci achieved suggestive significance (p < 10-6). GWAS signals were enriched in brain tissues, such as the anterior cingulate cortex, dorsolateral prefrontal cortex, entorhinal cortex, frontal cortex, hippocampus, and inferior temporal cortex. Cochlear cell types revealed no significant association with SIN deficits. SIN deficits were associated with various health traits, including neuropsychiatric, sensory, cognitive, metabolic, cardiovascular, and inflammatory conditions. A replication analysis was conducted on 242 healthy young adults. Self-reported speech perception, hearing thresholds (0.25-16 kHz), and distortion product otoacoustic emissions (1-16 kHz) were utilized for the replication analysis. 73 SNPs were replicated with a self-reported speech perception measure. 211 SNPs were replicated with at least one and 66 with at least two audiological measures. 12 SNPs near or within MAPT, GRM3, and HLA-DQA1 were replicated for all audiological measures. The present study highlighted a polygenic architecture underlying SIN deficits in individuals with self-reported normal hearing.

Toward Robust Functional Neuroimaging Genetics of Cognition.

A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms.SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10-100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.

Dorsal language stream anomalies in an inherited speech disorder.

Speech disorders are highly prevalent in the preschool years, but frequently resolve. The neurobiological basis of the most persistent and severe form, apraxia of speech, remains elusive. Current neuroanatomical models of speech processing in adults propose two parallel streams. The dorsal stream is involved in sound to motor speech transformations, while the ventral stream supports sound/letter to meaning. Data-driven theories on the role of these streams during atypical speech and language development are lacking. Here we provide comprehensive behavioural and neuroimaging data on a large novel family where one parent and 11 children presented with features of childhood apraxia of speech (the same speech disorder associated with FOXP2 variants). The genetic cause of the disorder in this family remains to be identified. Importantly, in this family the speech disorder is not systematically associated with language or literacy impairment. Brain MRI scanning in seven children revealed large grey matter reductions over the left temporoparietal region, but not in the basal ganglia, relative to typically-developing matched peers. In addition, we detected white matter reductions in the arcuate fasciculus (dorsal language stream) bilaterally, but not in the inferior fronto-occipital fasciculus (ventral language stream) nor in primary motor pathways. Our findings identify disruption of the dorsal language stream as a novel neural phenotype of developmental speech disorders, distinct from that reported in speech disorders associated with FOXP2 variants. Overall, our data confirm the early role of this stream in auditory-to-articulation transformations. 10.1093/brain/awz018_video1 awz018media1 6018582401001.

Maturation of vocal emotion recognition: Insights from the developmental and neuroimaging literature.

Emotions are implicitly expressed in both facial expressions and prosodic components of vocal communication. The ability to recognize nonverbal cues of emotion is an important feature of social competence that matures gradually across childhood and adolescence. Compared to the extensive knowledge about the development of emotion recognition (ER) from facial displays of emotion, relatively little is known about the maturation of this ability in the auditory domain. The current review provides an overview of knowledge about the development of vocal emotion recognition from behavioural studies, and neural mechanisms that might contribute to this maturational process. Youth are thought to reach adult-like vocal ER ability in early or late adolescence. At a neural level, several structural and functional changes occur in the adolescent brain that may impact the representation of emotional information. However, there is a paucity of developmental neuroimaging work directly examining neural prosody processing in youth. We speculate that brain areas relevant to vocal perception in adults may undergo age-related changes that map onto increased vocal ER capacity.

Phonological working memory and FOXP2.

The discovery and description of the affected members of the KE family (aKE) initiated research on how genes enable the unique human trait of speech and language. Many aspects of this genetic influence on speech-related cognitive mechanisms are still elusive, e.g. if and how cognitive processes not directly involved in speech production are affected. In the current study we investigated the effect of the FOXP2 mutation on Working Memory (WM). Half the members of the multigenerational KE family have an inherited speech-language disorder, characterised as a verbal and orofacial dyspraxia caused by a mutation of the FOXP2 gene. The core phenotype of the affected KE members (aKE) is a deficiency in repeating words, especially complex non-words, and in coordinating oromotor sequences generally. Execution of oromotor sequences and repetition of phonological sequences both require WM, but to date the aKE's memory ability in this domain has not been examined in detail. To do so we used a test series based on the Baddeley and Hitch WM model, which posits that the central executive (CE), important for planning and manipulating information, works in conjunction with two modality-specific components: The phonological loop (PL), specialized for processing speech-based information; and the visuospatial sketchpad (VSSP), dedicated to processing visual and spatial information. We compared WM performance related to CE, PL, and VSSP function in five aKE and 15 healthy controls (including three unaffected members of the KE family who do not have the FOXP2 mutation). The aKE scored significantly below this control group on the PL component, but not on the VSSP or CE components. Further, the aKE were impaired relative to the controls not only in motor (i.e. articulatory) output but also on the recognition-based PL subtest (word-list matching), which does not require speech production. These results suggest that the aKE's impaired phonological WM may be due to a defect in subvocal rehearsal of speech-based material, and that this defect may be due in turn to compromised speech-based representations.

Exploring a method for evaluation of preschool and school children with autism spectrum disorder through checking their understanding of the speaker's emotions with the help of prosody of the voice.

PURPOSE: We attempted to evaluate the ability of 125 preschool and school children with autism spectrum disorder (ASD children) to understand the intentions of those speaking to them using prosody of the voice, by comparing it with that of 119 typically developing children (TDC) and 51 development-age-matched children with attention deficit hyperactivity disorder (ADHD children), and to explore, based on the results, a method for objective evaluation of children with ASD in the early and later periods of childhood. METHODS: Phrases routinely used by children were employed in the task administered to the children, with the prosody of the voice speaking these phrases changed to express the four emotions (acceptance, rejection, bluff and fooling). RESULTS: The percentage of children with ASD who could correctly identify the emotion of "fooling" was significantly lower than that of TDC, at each developmental age (corresponding to middle kindergarten class to sixth year of elementary school). On the other hand, in the children with ADHD, while the correct answer rate for identifying the emotion of "fooling" was significantly lower than that in the TDC and higher than that in the ASD children at development ages corresponding to the early years of elementary school, it did not differ significantly from that in the TDC and was higher than that ASD children at development ages corresponding to the later years of elementary school. CONCLUSION: These results indicate that children with ASD find it particularly difficult to understand the emotion of fooling by listening to speech with discrepancy between the meaning of the phrases and the emotion expressed by the voice, although the prosody of the voice may serve as a key to understanding the emotion of the speakers. This finding also suggests that the prosody of the voice expressing this emotion (fooling) may be used for objective evaluation of children with ASD.

Common variation in the autism risk gene CNTNAP2, brain structural connectivity and multisensory speech integration.

Three lines of evidence motivated this study. 1) CNTNAP2 variation is associated with autism risk and speech-language development. 2) CNTNAP2 variations are associated with differences in white matter (WM) tracts comprising the speech-language circuitry. 3) Children with autism show impairment in multisensory speech perception. Here, we asked whether an autism risk-associated CNTNAP2 single nucleotide polymorphism in neurotypical adults was associated with multisensory speech perception performance, and whether such a genotype-phenotype association was mediated through white matter tract integrity in speech-language circuitry. Risk genotype at rs7794745 was associated with decreased benefit from visual speech and lower fractional anisotropy (FA) in several WM tracts (right precentral gyrus, left anterior corona radiata, right retrolenticular internal capsule). These structural connectivity differences were found to mediate the effect of genotype on audiovisual speech perception, shedding light on possible pathogenic pathways in autism and biological sources of inter-individual variation in audiovisual speech processing in neurotypicals.

Dyslexia risk gene relates to representation of sound in the auditory brainstem.

Dyslexia is a reading disorder with strong associations with KIAA0319 and DCDC2. Both genes play a functional role in spike time precision of neurons. Strikingly, poor readers show an imprecise encoding of fast transients of speech in the auditory brainstem. Whether dyslexia risk genes are related to the quality of sound encoding in the auditory brainstem remains to be investigated. Here, we quantified the response consistency of speech-evoked brainstem responses to the acoustically presented syllable [da] in 159 genotyped, literate and preliterate children. When controlling for age, sex, familial risk and intelligence, partial correlation analyses associated a higher dyslexia risk loading with KIAA0319 with noisier responses. In contrast, a higher risk loading with DCDC2 was associated with a trend towards more stable responses. These results suggest that unstable representation of sound, and thus, reduced neural discrimination ability of stop consonants, occurred in genotypes carrying a higher amount of KIAA0319 risk alleles. Current data provide the first evidence that the dyslexia-associated gene KIAA0319 can alter brainstem responses and impair phoneme processing in the auditory brainstem. This brain-gene relationship provides insight into the complex relationships between phenotype and genotype thereby improving the understanding of the dyslexia-inherent complex multifactorial condition.

Involvement of the Serotonin Transporter Gene in Accurate Subcortical Speech Encoding.

A flourishing line of evidence has highlighted the encoding of speech sounds in the subcortical auditory system as being shaped by acoustic, linguistic, and musical experience and training. And while the heritability of auditory speech as well as nonspeech processing has been suggested, the genetic determinants of subcortical speech processing have not yet been uncovered. Here, we postulated that the serotonin transporter-linked polymorphic region (5-HTTLPR), a common functional polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4), is implicated in speech encoding in the human subcortical auditory pathway. Serotonin has been shown as essential for modulating the brain response to sound both cortically and subcortically, yet the genetic factors regulating this modulation regarding speech sounds have not been disclosed. We recorded the frequency following response, a biomarker of the neural tracking of speech sounds in the subcortical auditory pathway, and cortical evoked potentials in 58 participants elicited to the syllable /ba/, which was presented >2000 times. Participants with low serotonin transporter expression had higher signal-to-noise ratios as well as a higher pitch strength representation of the periodic part of the syllable than participants with medium to high expression, possibly by tuning synaptic activity to the stimulus features and hence a more efficient suppression of noise. These results imply the 5-HTTLPR in subcortical auditory speech encoding and add an important, genetically determined layer to the factors shaping the human subcortical response to speech sounds. SIGNIFICANCE STATEMENT: The accurate encoding of speech sounds in the subcortical auditory nervous system is of paramount relevance for human communication, and it has been shown to be altered in different disorders of speech and auditory processing. Importantly, this encoding is plastic and can therefore be enhanced by language and music experience. Whether genetic factors play a role in speech encoding at the subcortical level remains unresolved. Here we show that a common polymorphism in the serotonin transporter gene relates to an accurate and robust neural tracking of speech stimuli in the subcortical auditory pathway. This indicates that serotonin transporter expression, eventually in combination with other polymorphisms, delimits the extent to which lifetime experience shapes the subcortical encoding of speech.

Investigating heritability of laterality and cognitive control in speech perception.

Several studies analyzing the ontogenetic origin of cerebral lateralization provide evidences for a genetic foundation of handedness in humans that is modulated by environmental influences. Since other forms of behavioral lateralization are less investigated, it is unclear as to how far different functions display similar heritability. But deeper knowledge is necessary to understand if and how developmental coupling of different functions is based on a shared genetic background or on the impact of environmental influences. Here, we investigated the heritability of language lateralization assessed with the dichotic listening task, as well as the heritability of cognitive control processes modulating performance in this task. Overall, 103 families consisting of both parents and offspring were tested with the non-forced, as well as the forced-right and forced-left condition of the forced attention dichotic listening task, implemented in the iDichotic smartphone app, developed at the University of Bergen, Norway. The results indicate that the typical right ear advantage in the dichotic listening task shows weak and non-significant heritability (h2=0.003; p=0.98). In contrast, cognitive factors, like attention focus (forced right condition: h2=0.36; p<0.01; forced left condition: h2=0.28; p<0.05) and cognitive control (Gain forced right: h2=0.39; p<0.01; Gain forced left: h2=0.49; p<0.01) showed stronger and significant heritability. These findings indicate a variable dependence of different aspects of a cognitive function on heritability and implicate a major contribution of non-genetic influences to individual language lateralization.

Knockdown of Dyslexia-Gene Dcdc2 Interferes with Speech Sound Discrimination in Continuous Streams.

UNLABELLED: Dyslexia is the most common developmental language disorder and is marked by deficits in reading and phonological awareness. One theory of dyslexia suggests that the phonological awareness deficit is due to abnormal auditory processing of speech sounds. Variants in DCDC2 and several other neural migration genes are associated with dyslexia and may contribute to auditory processing deficits. In the current study, we tested the hypothesis that RNAi suppression of Dcdc2 in rats causes abnormal cortical responses to sound and impaired speech sound discrimination. In the current study, rats were subjected in utero to RNA interference targeting of the gene Dcdc2 or a scrambled sequence. Primary auditory cortex (A1) responses were acquired from 11 rats (5 with Dcdc2 RNAi; DC-) before any behavioral training. A separate group of 8 rats (3 DC-) were trained on a variety of speech sound discrimination tasks, and auditory cortex responses were acquired following training. Dcdc2 RNAi nearly eliminated the ability of rats to identify specific speech sounds from a continuous train of speech sounds but did not impair performance during discrimination of isolated speech sounds. The neural responses to speech sounds in A1 were not degraded as a function of presentation rate before training. These results suggest that A1 is not directly involved in the impaired speech discrimination caused by Dcdc2 RNAi. This result contrasts earlier results using Kiaa0319 RNAi and suggests that different dyslexia genes may cause different deficits in the speech processing circuitry, which may explain differential responses to therapy. SIGNIFICANCE STATEMENT: Although dyslexia is diagnosed through reading difficulty, there is a great deal of variation in the phenotypes of these individuals. The underlying neural and genetic mechanisms causing these differences are still widely debated. In the current study, we demonstrate that suppression of a candidate-dyslexia gene causes deficits on tasks of rapid stimulus processing. These animals also exhibited abnormal neural plasticity after training, which may be a mechanism for why some children with dyslexia do not respond to intervention. These results are in stark contrast to our previous work with a different candidate gene, which caused a different set of deficits. Our results shed some light on possible neural and genetic mechanisms causing heterogeneity in the dyslexic population.

Auditory neuropathy in Brown-Vialetto-Van Laere syndrome due to riboflavin transporter RFVT2 deficiency.

AIM: Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown-Vialetto-Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy. METHOD: We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual. RESULTS: Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual. INTERPRETATION: Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation.

Enhanced procedural learning of speech sound categories in a genetic variant of FOXP2.

A mutation of the forkhead box protein P2 (FOXP2) gene is associated with severe deficits in human speech and language acquisition. In rodents, the humanized form of FOXP2 promotes faster switching from declarative to procedural learning strategies when the two learning systems compete. Here, we examined a polymorphism of FOXP2 (rs6980093) in humans (214 adults; 111 females) for associations with non-native speech category learning success. Neurocomputational modeling results showed that individuals with the GG genotype shifted faster to procedural learning strategies, which are optimal for the task. These findings support an adaptive role for the FOXP2 gene in modulating the function of neural learning systems that have a direct bearing on human speech category learning.

Music training and speech perception: a gene-environment interaction.

Claims of beneficial side effects of music training are made for many different abilities, including verbal and visuospatial abilities, executive functions, working memory, IQ, and speech perception in particular. Such claims assume that music training causes the associations even though children who take music lessons are likely to differ from other children in music aptitude, which is associated with many aspects of speech perception. Music training in childhood is also associated with cognitive, personality, and demographic variables, and it is well established that IQ and personality are determined largely by genetics. Recent evidence also indicates that the role of genetics in music aptitude and music achievement is much larger than previously thought. In short, music training is an ideal model for the study of gene-environment interactions but far less appropriate as a model for the study of plasticity. Children seek out environments, including those with music lessons, that are consistent with their predispositions; such environments exaggerate preexisting individual differences.

Phenotypic and genetic associations between reading comprehension, decoding skills, and ADHD dimensions: evidence from two population-based studies.

BACKGROUND: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and hyperactivity/impulsivity in early schooling and compare them to those with decoding skills. METHODS: Data were collected in two population-based samples of twins (Quebec Newborn Twin Study - QNTS) and singletons (Quebec Longitudinal Study of Child Development - QLSCD) totaling ≈ 2300 children. Reading was assessed with normed measures in second or third grade. Teachers assessed ADHD dimensions in kindergarten and first grade. RESULTS: Both decoding and reading comprehension were correlated with ADHD dimensions in a similar way: associations with inattention remained after controlling for the other ADHD dimension, behavior disorder symptoms and nonverbal abilities, whereas associations with hyperactivity/impulsivity did not. Genetic modeling showed that decoding and comprehension largely shared the same genetic etiology at this age and that their associations with inattention were mostly explained by shared genetic influences. CONCLUSION: Both reading comprehension and decoding are uniquely associated with inattention through a shared genetic etiology.

Dopamine receptor D4 (DRD4) gene modulates the influence of informational masking on speech recognition.

Listeners vary substantially in their ability to recognize speech in noisy environments. Here we examined the role of genetic variation on individual differences in speech recognition in various noise backgrounds. Background noise typically varies in the levels of energetic masking (EM) and informational masking (IM) imposed on target speech. Relative to EM, release from IM is hypothesized to place greater demand on executive function to selectively attend to target speech while ignoring competing noises. Recent evidence suggests that the long allele variant in exon III of the DRD4 gene, primarily expressed in the prefrontal cortex, may be associated with enhanced selective attention to goal-relevant high-priority information even in the face of interference. We investigated the extent to which this polymorphism is associated with speech recognition in IM and EM conditions. In an unscreened adult sample (Experiment 1) and a larger screened replication sample (Experiment 2), we demonstrate that individuals with the DRD4 long variant show better recognition performance in noise conditions involving significant IM, but not in EM conditions. In Experiment 2, we also obtained neuropsychological measures to assess the underlying mechanisms. Mediation analysis revealed that this listening condition-specific advantage was mediated by enhanced executive attention/working memory capacity in individuals with the long allele variant. These findings suggest that DRD4 may contribute specifically to individual differences in speech recognition ability in noise conditions that place demands on executive function.

Speech sound processing deficits and training-induced neural plasticity in rats with dyslexia gene knockdown.

In utero RNAi of the dyslexia-associated gene Kiaa0319 in rats (KIA-) degrades cortical responses to speech sounds and increases trial-by-trial variability in onset latency. We tested the hypothesis that KIA- rats would be impaired at speech sound discrimination. KIA- rats needed twice as much training in quiet conditions to perform at control levels and remained impaired at several speech tasks. Focused training using truncated speech sounds was able to normalize speech discrimination in quiet and background noise conditions. Training also normalized trial-by-trial neural variability and temporal phase locking. Cortical activity from speech trained KIA- rats was sufficient to accurately discriminate between similar consonant sounds. These results provide the first direct evidence that assumed reduced expression of the dyslexia-associated gene KIAA0319 can cause phoneme processing impairments similar to those seen in dyslexia and that intensive behavioral therapy can eliminate these impairments.

Abnormal semantic processing in females with fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, affects fragile X (FMR1) gene premutation carriers in late life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event-related potentials (ERPs) and neuropsychological testing. Sixty-one females (34 FXTAS, Mage = 62.7; 27 controls, Mage = 60.4) were studied with 32-channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated approximately 10-140 seconds later. N400 and P600 amplitude data were submitted to analysis of covariance. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. Event-related potential analyses showed a significant reduction of the N400 congruity effect (incongruous - congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult.

FOXP2 variation modulates functional hemispheric asymmetries for speech perception.

Left-hemispheric language dominance is a well-known characteristic of the human language system, but the molecular mechanisms underlying this crucial feature of vocal communication are still far from being understood. The forkhead box P2 gene FOXP2, which has been related to speech development, constitutes an interesting candidate gene in this regard. Therefore, the present study was aimed at investigating effects of variation in FOXP2 on individual language dominance. To this end, we used a dichotic listening and a visual half-field task in a sample of 456 healthy adults. The FOXP2 SNPs rs2396753 and rs12533005 were found to be significantly associated with the distribution of correct answers on the dichotic listening task. These results show that variation in FOXP2 may contribute to the inter-individual variability in hemispheric asymmetries for speech perception.

6p25 interstitial deletion in two dizygotic twins with gyral pattern anomaly and speech and language disorder.

Submicroscopic 6p25 deletion is now recognized as a clinically identifiable syndrome, characterized by intellectual disability, language impairment, hearing deficit, craniofacial, ophthalmologic, cardiac, and varying central nervous system anomalies. We report on two dyzogotic twins with a maternal segregating hemizygous interstitial deletion on chromosome 6p25.1, spanning 0.9 kb; the smallest ever reported. Both had dysmorphic features (prominence of the metopic suture, synophrys, hypertelorism, down-slanting palpebral fissures, tented mouth), and a distinct brain MRI, showing a focal significant increase of the right peri-frontal subarachnoid space, with shallow sulci and a mild anomaly of the gyral pattern. Such brain anomaly has never been reported in association with del 6p25. Both propositi had a borderline-mild intellectual disability, speech and language difficulties, and behavior abnormalities. Their mother, formally tested, had a borderline cognitive impairment. Although none of the genes mapping to the deleted region are apparently related to the phenotype, LYRM4 resulted down-regulated in the cerebellar cortex of schizophrenia patients compared with controls, and Lyrm4 was down-regulated in the prefrontal cortex of mice with microdeletions in the locus syntenic to human 22q11.2 patients affected by schizophrenia. These data are in agreement with the emerging concept that similar CNVs are pathogenic in patients affected by distinct neurological diseases, and that these loci are more general risk factors for different disorders. The resemblance of our patients to those with the more extensive 6p25.1p25.3 terminal deletion suggests that the gene/s responsible for the physical phenotype should reside in the 6p25.1 genomic region.