Monogenic and chromosomal causes of isolated speech and language impairment

Barnett, Christopher; Bon, Bregje W.M. van

doi:10.1136/jmedgenet-2015-103161

Cited by 16 publications

(16 citation statements)

References 140 publications

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“…In contrast, no significant association with global burden of CNVs in language and reading traits was found in another study. Multiple case reports have implicated rare CNVs as causative for language phenotypes (reviewed in ). For example, deletions at the 16p11.2 have been reported as a penetrant cause of childhood apraxia of speech.…”

Section: Introductionmentioning

confidence: 85%

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Enrichment of rare copy number variation in children with developmental language disorder

et al. 2018

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Developmental language disorder (DLD) is a common neurodevelopmental disorder with largely unknown etiology. Rare copy number variants (CNVs) have been implicated in the genetic architecture of other neurodevelopmental disorders (NDDs), which have led to clinical genetic testing recommendations for these disorders; however, the evidence is still lacking for DLD. We analyzed rare and de novo CNVs in 58 probands with severe DLD, their 159 family members and 76 Swedish typically developing children using high-resolution microarray. DLD probands had larger rare CNVs as measured by total length (P = .05), and average length (P = .04). In addition, the rate of rare CNVs overlapping coding genes was increased (P = .03 and P = .01) and in average more genes were affected (P = .006 and P = .03) in the probands and their siblings, respectively. De novo CNVs were found in 4.8% DLD probands (2/42) and 2.4% (1/42) siblings. Clinically significant CNVs or chromosomal anomalies were found in 6.9% (4/58) of the probands of which 2 carried 16p11.2 deletions. We provide further evidence that rare CNVs contribute to the etiology of DLD in loci that overlap with other NDDs. Based on our results and earlier literature, families with DLD should be offered molecular genetic testing as a routine in their clinical follow-up.

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Section: Introductionmentioning

confidence: 85%

“…Due to the limited evidence of rare CNVs in DLD, the affected children are rarely genetically evaluated using CMA. For DLD, only one study has investigated the contribution of CNVs to the genetic landscape of the disorder concluding that common inherited CNVs are significantly enriched in DLD.…”

Section: Introductionmentioning

confidence: 99%

Enrichment of rare copy number variation in children with developmental language disorder

et al. 2018

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“…Furthermore, recent reports of germline chromosomal deletions and truncating mutations in SETBP1 show that loss-of-function mutations in this gene cause a completely different phenotype from SGS [52]. Clinically, individuals with these genetic lesions present a phenotype characterized by a complete lack of expressive speech with intact receptive language abilities, decreased fine motor skills, subtle dysmorphisms and hyperactivity and autistic traits [53]. …”

Section: Discussionmentioning

confidence: 99%

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

et al. 2017

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Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

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“…Numerous genetic factors contribute to speech and language development and impairment (Barnett & van Bon, 2015; Graham & Fisher, 2015). In the most recent analysis of the Deciphering Developmental Disorders (DDD) study (Deciphering Developmental Disorders Study, 2015), the extent of speech delay in patients with developmental disorders has been shown to statistically increase the likelihood of finding a damaging de novo mutation (Deciphering Developmental Disorders Study, 2017).…”

Section: Introductionmentioning

confidence: 99%

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

Soblet

Dimov

Kalckreuth

et al. 2017

American J of Med Genetics Pt A

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We report the case of a 7‐year‐old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.

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Monogenic and chromosomal causes of isolated speech and language impairment

Cited by 16 publications

References 140 publications

Enrichment of rare copy number variation in children with developmental language disorder

Enrichment of rare copy number variation in children with developmental language disorder

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

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