CNTNAP2 gene polymorphisms in autism spectrum disorder and language impairment among Bangladeshi children: a case-control study combined with a meta-analysis.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by communication deficits, impaired social interactions, repetitive and stereotyped behaviors with restricted interests, and connected with the interaction between environmental factors and genetic vulnerability. CNTNAP2 gene has been extensively investigated for ASD and related neurodevelopment diseases. However, previous studies have resulted in an inconsistent outcome. Based on this fact, we conducted a case-control study followed by a meta-analysis to investigate the association of rs7794745 and rs2710102 polymorphisms with ASD. A total of 216 autistic children and 240 healthy volunteers were recruited, and genotyping was performed using the PCR-RFLP method. We observed that SNP rs7794745 revealed a significantly (p < 0.05) increased association with the development of ASD in children in all genetic models. No significant association was found for rs2710102 with ASD. Besides, rs2710102 exhibited a significant association with language impairment in TC genotype, C allele, and dominant model. From the meta-analysis of both SNPs, we found a significant association in codominant 1, 2, and the dominant model of rs2710102 and codominant 1 and dominant model of rs7794745 with ASD. Our case-control study suggests that rs7794745 polymorphism is associated with ASD, while rs2710102 is correlated with language impairment. Moreover, meta-analysis results indicated the association between both rs7794745 and rs2710102 polymorphisms and ASD.

A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures.

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

Characterization of an unbalanced translocation causing 3q28qter duplication and 10q26.2qter deletion in a patient with global developmental delay and self-injury.

Chromosomal structural variation can cause severe neurodevelopmental and neuropsychiatric phenotypes. Here we present a nonverbal female adolescent with severe stereotypic movement disorder with severe problem behavior (e.g., self-injurious behavior, aggression, and disruptive and destructive behaviors), autism spectrum disorder, severe intellectual disability, attention deficit hyperactivity disorder, and global developmental delay. Previous cytogenetic analysis revealed balanced translocations present in the patient's apparently normal mother. We hypothesized the presence of unbalanced translocations in the patient due to maternal history of spontaneous abortions. Whole-genome sequencing and whole-genome optical mapping, complementary next-generation genomic technologies capable of the accurate and robust detection of structural variants, identified t(3;10), t(10;14), and t(3;14) three-way balanced translocations in the mother and der(10)t(3;14;10) and der(14)t(3;14;10) translocations in the patient. Instead of a t(3;10), she inherited a normal maternal copy of Chromosome 3, resulting in an unbalanced state of a 3q28qter duplication and 10q26.2qter deletion. Copy-imbalanced genes in one or both of these regions, such as DLG1, DOCK1, and EBF3, may contribute to the patient's phenotype that spans neurodevelopmental, musculoskeletal, and psychiatric domains, with the possible contribution of a maternally inherited 15q13.2q13.3 deletion.

A genetic window to auditory-verbal problems in bipolar disorder.

Bipolar disorder is a high prevalent psychiatric condition entailing recurrent episodes of elevated mood and depression, but also diverse cognitive problems. One deficit observed in patients concerns to auditory-verbal processing. Being a hereditary condition with a complex genetic architecture, it is not clear which genes contribute to this deficit. We show that candidates for bipolar disorder significantly overlap with candidates for clinical conditions resulting from a deficit in the phonological loop of working memory, particularly, developmental dyslexia and specific language impairment. The overlapping genes are involved in aspects of brain development and function (particularly, brain oscillations) potentially underlying phonological processing and accordingly, emerge as promising candidates for auditory-verbal deficits in bipolar disorder.

Heritability of Specific Language Impairment and Nonspecific Language Impairment at Ages 4 and 6 Years Across Phenotypes of Speech, Language, and Nonverbal Cognition.

Purpose Early language and speech acquisition can be delayed in twin children, a twinning effect that diminishes between 4 and 6 years of age in a population-based sample. The purposes of this study were to examine how twinning effects influence the identification of children with language impairments at 4 and 6 years of age, comparing children with specific language impairment (SLI) and nonspecific language impairment (NLI); the likelihood that affectedness will be shared within monozygotic versus dizygotic twin pairs; and estimated levels of heritability for SLI and NLI. Twinning effects are predicted to result in elevated rates of language impairments in twins. Method The population-based twin sample included 1,354 children from 677 twin pairs, 214 monozygotic and 463 dizygotic, enrolled in a longitudinal study. Nine phenotypes from the same comprehensive direct behavioral assessment protocol were investigated at 4 and 6 years of age. Twinning effects were estimated for each phenotype at each age using structural equation models estimated via diagonally weighted least squares. Heritabilities were calculated for SLI and NLI. Results As predicted, the twinning effect increased the percentage of affected children in both groups across multiple language phenotypes, an effect that diminished with age yet was still not aligned to singleton age peers. Substantial heritability estimates replicated across language phenotypes and increased with age, even with the most lenient definition of affectedness, at -1 SD. Patterns of outcomes differed between SLI and NLI groups. Conclusions Nonverbal IQ is not on the same causal pathway as language impairments. Twinning effects on language acquisition affect classification of 4- and 6-year-old children as SLI and NLI, and heritability is most consistent in the SLI group. Clinical practice requires monitoring language acquisition of twins to avoid misdiagnosis when young or a missed diagnosis of language impairments at school entry.

Language deficits in specific language impairment, attention deficit/hyperactivity disorder, and autism spectrum disorder: An analysis of polygenic risk.

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome-wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome-wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age-matched controls and perform regression analyses across groups. The SLI-trained PRS significantly predicted risk in the SLI case-control group (adjusted R2 = 6.24%; P = 0.024) but not in the ASD or ADHD case-control groups (adjusted R2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common-variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369-381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome-wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders.

Language impairment in primary progressive aphasia and other neurodegenerative diseases.

Primary progressive aphasia (PPA) is a progressive neurodegenerative disease that disrupts the language capacity of an individual by selectively affecting the language network of brain. Although aphasic literature is replete with reports of brain damage responsible for various types of PPA, it does not provide a comprehensive understanding of whether PPA is an independent pathological condition or an atypical syndrome of neurodegenerative diseases (NDD). To address this ambiguity, we provide a detailed description of PPA, its variants and their brain anatomy. Subsequently, we unravel the relationship between PPA and NDDs like Alzheimer's, Parkinson's and Dyslexia. To substantiate the relationship further, we also provide a brief account of their genetic aetiology. In the final section, we offer an exhaustive approach towards the treatment of PPA by combining the existing language the rapies with clinical and pharmacological interventions.

A genome-wide analysis in consanguineous families reveals new chromosomal loci in specific language impairment (SLI).

Language is a uniquely human ability, and failure to attain this ability can have a life-long impact on the affected individuals. This is particularly true for individuals with specific language impairment (SLI), which is defined as an impairment in normal language development in the absence of any other developmental disability. Although SLI displays high heritability, family-based linkage studies have been hampered by an unclear mode of Mendelian segregation, variable disease penetrance, and heterogeneity of diagnostic criteria. We performed genome-wide parametric linkage analysis and homozygosity mapping in 14 consanguineous families from Pakistan segregating SLI. Linkage analysis revealed a multipoint LOD score of 4.18 at chromosome 2q in family PKSLI05 under a recessive mode of inheritance. A second linkage score of 3.85 was observed in family PKSLI12 at a non-overlapping locus on chromosome 2q. Two other suggestive linkage loci were found in family PKSLI05 on 14q and 22q with LOD scores of 2.37 and 2.23, respectively, that were also identified in homozygosity mapping. Reduction to homozygosity was observed on chromosomes 2q, 5p, 8q, 14q, 17q, and 22q. Each homozygosity region occurred in multiple PKSLI families. We report new SLI loci on chromosomes 2 and 8 and confirm suggestive SLI linkage loci on chromosomes 5, 14, 17, and 22 reported previously in the population of Robinson Crusoe Island. These findings indicate that linkage and homozygosity mapping in consanguineous families can improve genetic analyses in SLI and suggest the involvement of additional genes in the causation of this disorder.