A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype

Beunders, Gea; Kamp, Jiddeke van de; Vasudevan, Pradeep; Morton, Jenny; Smets, Katrien; Kleefstra, Tjitske; Munnik, Sonja A de; Schuurs-Hoeijmakers, Janneke; Ceulemans, Berten; Zollino, Marcella; Hoffjan, Sabine; Wieczorek, Stefan; So, Joyce; Mercer, Leanne; Walker, T S; Velsher, Lea; Parker, Michael; Magee, Alex; Elffers, Bart; Kooy, R. Frank; Yntema, Helger G.; Meijers-Heijboer, E. J.; Sistermans, Erik A.

doi:10.1136/jmedgenet-2015-103601

Cited by 53 publications

(83 citation statements)

References 29 publications

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“…The 7q11.22 deletion encoppasses the entire intron 2 (which spans about 200 kb) of the AUTS2 gene (OMIM:*607270). Heterozygous AUTS2 variants have been previously associated with a specific syndromic condition (Beunders et al, ), which distinctive features are absent in our patient. Furthermore, pathogenic deletions within AUTS2 were reported to affect at least part of an exon.…”

Section: Clinical Reportsupporting

confidence: 52%

A novel truncating variant within exon 7 of KAT6B associated with features of both Say–Barber–Bieseker–Young–Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B‐related disorders

Marangi¹,

Giacomo

Lattante³

et al. 2017

American J of Med Genetics Pt A

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KAT6B sequence variants have been identified in both patients with the Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16-18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.

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Section: Clinical Reportsupporting

confidence: 52%

A novel truncating variant within exon 7 of KAT6B associated with features of both Say–Barber–Bieseker–Young–Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B‐related disorders

Marangi¹,

Giacomo

Lattante³

et al. 2017

American J of Med Genetics Pt A

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“…This group consisted of three individuals (Patient C was too young to complete the SRS‐2), one with a deletion spanning the entire WBSCR but extending beyond AUTS2 (Patient B) and two individuals with a deletion that spared GTF2i within the WBSCR and AUTS2 (Patients D and E). Deletions and/or point mutations in GTF2i and AUTS2 have been associated with impaired social functioning (Beunders et al, ; Borralleras, Sahun, Perez‐Jurado, & Campuzano, ; Crespi & Hurd, ; Jolley et al, ). When the centromeric‐deletion group was divided, the patient with the deletion containing GTF2i and AUTS2 (Patient B) had a social motivation score similar to the patient with the bidirectional deletion, while the patients with a deletion sparing GTF2i and AUTS2 (Patients D and E) had lower T scores (less impairment) in all areas than the typical‐deletion group (Supporting Information Figure B).…”

Section: Resultsmentioning

confidence: 99%

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams–Beuren syndrome

Lugo

Wong

Billington

et al. 2020

American J of Med Genetics Pt A

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Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature.Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation. K E Y W O R D S atypical deletion, autism spectrum, microcephaly, phenotype, social behavior, Williams-Beuren syndrome

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“…In 90% (9/10) of children from the mtdel-ASD cohort, we found rare SNVs in ASD-associated genes (Table 4 ). A rare mutation was detected in AUTS2 in which deletions are inherited in an autosomal dominant manner and are associated with neurological symptoms including intellectual disability and developmental delay [ 49 ]. In a modest study of 13 cases of ASD associated with AUTS2 alterations, only one patient had a nonsense mutation; all the other patients had a deletion [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…A rare mutation was detected in AUTS2 in which deletions are inherited in an autosomal dominant manner and are associated with neurological symptoms including intellectual disability and developmental delay [ 49 ]. In a modest study of 13 cases of ASD associated with AUTS2 alterations, only one patient had a nonsense mutation; all the other patients had a deletion [ 49 ]. The significance of the missense mutation identified in our study is uncertain (her mother harbours the mutation as well); however, clinical symptoms of the patient correlate with the phenotype of previously published AUTS2 mutations.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion

et al. 2018

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BackgroundThe etiology of autism spectrum disorders (ASD) is very heterogeneous. Mitochondrial dysfunction has been described in ASD; however, primary mitochondrial disease has been genetically proven in a small subset of patients. The main goal of the present study was to investigate correlations between mitochondrial DNA (mtDNA) changes and alterations of genes associated with mtDNA maintenance or ASD.MethodsSixty patients with ASD and sixty healthy individuals were screened for common mtDNA mutations. Next generation sequencing was performed on patients with major mtDNA deletions (mtdel-ASD) using two gene panels to investigate nuclear genes that are associated with ASD or are responsible for mtDNA maintenance. Cohorts of healthy controls, ASD patients without mtDNA alterations, and patients with mitochondrial disorders (non-ASD) harbouring mtDNA deletions served as comparison groups.ResultsMtDNA deletions were confirmed in 16.6% (10/60) of patients with ASD (mtdel-ASD). In 90% of this mtdel-ASD children we found rare SNVs in ASD-associated genes (one of those was pathogenic). In the intergenomic panel of this cohort one likely pathogenic variant was present. In patients with mitochondrial disease in genes responsible for mtDNA maintenance pathogenic mutations and variants of uncertain significance (VUS) were detected more frequently than those found in patients from the mtdel-ASD or other comparison groups. In healthy controls and in patients without a mtDNA deletion, only VUS were detected in both panel.ConclusionsMtDNA alterations are more common in patients with ASD than in control individuals. MtDNA deletions are not isolated genetic alterations found in ASD; they coexist either with other ASD-associated genetic risk factors or with alterations in genes responsible for intergenomic communication. These findings indicate that mitochondrial dysfunction is not rare in ASD. The occurring mtDNA deletions in ASD may be mostly a consequence of the alterations of the causative culprit genes for autism or genes responsible for mtDNA maintenance, or because of the harmful effect of environmental factors.Electronic supplementary materialThe online version of this article (10.1186/s12993-018-0135-x) contains supplementary material, which is available to authorized users.

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A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype

Cited by 53 publications

References 29 publications

A novel truncating variant within exon 7 of KAT6B associated with features of both Say–Barber–Bieseker–Young–Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B‐related disorders

A novel truncating variant within exon 7 of KAT6B associated with features of both Say–Barber–Bieseker–Young–Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B‐related disorders

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams–Beuren syndrome

Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion

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