De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Cappuccio, Gerarda; Sayou, Camille; Tanno, Pauline Le; Tisserant, Émilie; Bruel, Ange‐Line; Kennani, Sara El; Sá, Joaquim; Low, Karen; Dias, Cristina; Havlovičová, Markéta; Hančárová, Miroslava; Eichler, Evan E.; Devillard, Françoise; Moutton, Sébastien; Van-Gils, Julien; Dubourg, Christèle; Odent, Sylvie; Gérard, Bénédicte; Piton, Amélie; Yamamoto, Toshiyuki; Okamoto, Nobuhiko; Firth, Helen V.; Metcalfe, Kay; Moh, Anna; Chapman, Kimberly A.; Aref‐Eshghi, Erfan; Kerkhof, Jennifer; Torella, Annalaura; Nigro, Vincenzo; Perrin, Laurence; Piard, Juliette; Guyader, Gwenaël Le; Jouan, Thibaud; Thauvin‐Robinet, Christel; Duffourd, Yannis; George‐Abraham, Jaya K.; Buchanan, Catherine A.; Williams, Denise; Kini, Usha; Wilson, Kate; Sousa, Sérgio B.; Hennekam, Raoul C. M.; Sadiković, Bekim; Thévenon, Julien; Govin, Jérôme; Vitobello, Antonio; Brunetti‐Pierri, Nicola

doi:10.1038/s41436-020-0898-y

Cited by 33 publications

(28 citation statements)

References 42 publications

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“…It may be that the three negative distal SRCAP frameshift variants escape NMD and, therefore, with the AT-hooks intact, result in a functional protein. 12 Unfortunately, no suitable three-dimensional SRCAP complex structure is currently available to evaluate the role of the distal part of the protein. If a functional protein is produced, the clinical features seen in these individuals might be caused by another yet unknown variant.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work in SMARCA2 shows correlations between variant location, DNAm signature, and clinical phenotype. 12 For SRCAP, it is clear there is a genotype-epigenotype-phenotype correlation, with different truncating variant locations within the gene associated with distinct clinical presentations and DNAm signatures.…”

Section: Discussionmentioning

confidence: 99%

“…8 Although SRCAP is widely studied in the context of FLHS, 3 the consequences of SRCAP variants located outside of the FLHS-causing locus are poorly understood, despite their increasing identification through next generation sequencing Different pathogenic variant types and locations within the same gene can be associated with distinct neurodevelopmental disorders. [9][10][11][12][13] When these occur in epigenetic regualtory genes, DNA methylation (DNAm) is an emerging functional tool to identify and characterize such disorders using specific patterns of genome-wide DNAm in peripheral blood which we call DNAm signatures. 14 To date, we and others have described >50 DNAm signatures associated with epigenetic regulatory genes.…”

Section: Introductionmentioning

confidence: 99%

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Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Rots¹,

Chater‐Diehl²,

Dingemans³

et al. 2021

The American Journal of Human Genetics

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Summary Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein ( SRCAP ) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo ) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS SRCAP -related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP , there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Rots¹,

Chater‐Diehl²,

Dingemans³

et al. 2021

The American Journal of Human Genetics

Self Cite

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“…It has been widely appreciated that many rare diseases of the epigenetic machinery demonstrate significant phenotype overlap. Individuals presented here have craniofacial dysmorphisms, and some facial features overlap with SMARCA2 -associated blepharophimosis intellectual disability syndrome ( 57 ), including blepharophimosis, short palpebral fissures, epicanthal folds, high arched and sparse eyebrows, and short metacarpals. Recently, pathogenic variants of BPTF , encoding a noncatalytic subunit of ISWI complex, have been implicated in a neurodevelopmental disorder ( 18 ).…”

Section: Discussionmentioning

confidence: 95%

Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

et al. 2021

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Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

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“…Although SMARCA5 -associated neurological complications are generally mild, postnatal proportionate short stature and microcephaly are rather predominant with standard deviations ranging from −2 to −4.78 for height, and −2 to −6.21 for head circumference, in 8/10 probands. Individuals presented here have craniofacial dysmorphisms and some facial features overlap with SMARCA2 -associated blepharophimosis intellectual disability syndrome ( 56 ), including blepharophimosis, short palpebral fissures, epicanthal folds, high arched and sparse eyebrows, and short metacarpals. Overall, individuals with the SMARCA5 -associated phenotypes appear to share similar dysmorphic features and clinical histories, including blepharophimosis, short palpebral fissures, periorbital fullness, wide/high nasal bridge, a thin or tented upper lip, short/flat philtrum, high arched, sparse, or medial flaring eyebrows, and hallux valgus, but each of the shared clinical findings is relatively non-specific.…”

Section: Discussionmentioning

confidence: 96%

Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

Liu

Wang

Gong

et al. 2020

Preprint

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Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature, and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

show abstract

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Cited by 33 publications

References 42 publications

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

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