Intrachromosomal 3p Insertion as a Cause of Reciprocal Pure Interstitial Deletion and Duplication in Two Siblings: Further Delineation of the Emerging Proximal 3p Deletion Syndrome

Lloveras, Elisabet; Vendrell, Teresa; Fernández, Asunción; Castells, Núria; Cueto, A.; Campo, Miguel del; Hernándo, Cristina; Villa, Olaya; Plaja, Alberto

doi:10.1159/000375184

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…Medical features of individuals with FOXP1 mutations reported in the literature vary widely and include brain and cardiac malformations, hypotonia, strabismus, and obesity [ 2 , 4 , 5 , 7 , 16 , 33 , 34 ]. Dysmorphic features associated with FOXP1 syndrome appear to be mild and inconsistent.…”

Section: Introductionmentioning

confidence: 99%

Prospective investigation of FOXP1 syndrome

et al. 2017

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BackgroundHaploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments.MethodsGenetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5–17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1.ResultsWe have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections.ConclusionsThis study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.Electronic supplementary materialThe online ver...

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Section: Introductionmentioning

confidence: 99%

Prospective investigation of FOXP1 syndrome

et al. 2017

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“…Reinforcing this hypothesis, previous reports have associated brain transcripts levels alterations on this TF in patients diagnosed with BD, schizophrenia and other mood‐related disorders (Ben‐Shachar & Karry, ; Pinacho et al., ; Shi et al., ; Shyn et al., ; Tam et al., ). Analyzing FOXP1 (variants associated with obesity could disturb the binding site of this TF) has been previously associated with speech development, and deleterious genetic variants are known to cause FOXP1 syndrome (Siper et al., ); patients with this syndrome have psychiatric alterations and almost 30% of them are obese (Le Fevre et al., ; Lloveras et al., ), suggesting a possible link between FOXP1 and obesity. FOXP1 is a TF critical in the fate of adult striatum medium spiny neurons projection and its transcript is highly up‐regulated in the whole ganglionic eminence (Precious et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…). Analyzing FOXP1 (variants associated with obesity could disturb the binding site of this TF) has been previously associated with speech development, and deleterious genetic variants are known to cause FOXP1 syndrome(Siper et al, 2017); patients with this syndrome have psychiatric alterations and almost 30% of them are obese (LeFevre et al, 2013;Lloveras et al, 2014), suggesting a possible link between FOXP1 and obesity. FOXP1 is a TF critical in the fate of adult striatum medium spiny neurons projection and its transcript is highly up-regulated in the whole ganglionic eminence…”

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confidence: 99%

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

et al. 2019

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Introduction Several studies indicate that polygenic obesity is linked to fat‐mass and obesity‐associated ( FTO ) genetic variants. Nevertheless, the link between variants in FTO and mental disorders has been barely explored. The present work aims to determine whether FTO genetic variants are associated with bipolar disorder and obesity, and to perform an in silico prediction of variant‐dependent functional impact on the developing brain transcriptome. Methods Four hundred and forty‐six Mexican mestizos were included in a genetic association analysis. SNP ‐sequence kernel association test and linear mixed models were implemented for genetic association assessment. For functional impact prediction, we analyzed the mapping of regulatory elements, the modification of binding sites of transcription factors and the expression of transcription factors in the brain developing transcriptome, searching on different databases. Results In the set‐based analysis, we found different associated regions to BD (bipolar disorder) and obesity. The promoter flanking region of FTO intron 1 was associated with differential effects on BMI , while intron 2 of RPGRIP 1L and FTO upstream regions were associated with BD . The prediction analysis showed that FTO BD ‐associated variants disturb binding sites of SP 1 and SP 2; obesity‐associated variants, on the other hand, disturb binding sites of FOXP 1, which are transcription factors highly expressed during prenatal development stages of the brain. Conclusion Our results suggest a possible effect of FTO variants on neurodevelopment in obesity and bipolar disorder, which gives new insights into the molecular mechanism underlying this association.

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Digital Karyotyping with Whole Genomic Sequencing for Complex Congenital Disorder

Chen

Liu

et al. 2015

Journal of Genetics and Genomics

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Intrachromosomal 3p Insertion as a Cause of Reciprocal Pure Interstitial Deletion and Duplication in Two Siblings: Further Delineation of the Emerging Proximal 3p Deletion Syndrome

Cited by 6 publications

References 13 publications

Prospective investigation of FOXP1 syndrome

Prospective investigation of FOXP1 syndrome

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

Digital Karyotyping with Whole Genomic Sequencing for Complex Congenital Disorder

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