Novel SMC1A frameshift mutations in children with developmental delay and epilepsy

Goldstein, Jessica; Tim‐Aroon, Thipwimol; Shieh, Joseph T.C.; Merrill, Michelle; Deeb, Kristin K.; Zhang, Shulin Na; Bass, Nancy; Bedoyan, Jirair K.

doi:10.1016/j.ejmg.2015.09.007

Cited by 27 publications

(33 citation statements)

References 28 publications

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“…Together with three other reported females with a LoF mutation in SMC1A, currently five females are known to date (15,16). For two of five females, functional data at mRNA processing levels have clearly showed the LoF effect of the mutation.…”

Section: Discussionmentioning

confidence: 77%

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De novo loss‐of‐function mutations in X‐linked SMC1A cause severe ID and therapy‐resistant epilepsy in females: expanding the phenotypic spectrum

Jansen¹,

Kleefstra²,

Willemsen³

et al. 2016

Clinical Genetics

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De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.

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Section: Discussionmentioning

confidence: 77%

“…In four of five patients, additional de novo mutations were identified. Whereas, these are reported to be neutral , an (added) contribution of these variants to the clinical phenotype cannot formerly be excluded. Notably, de novo LoF mutations have never been reported in control individuals .…”

Section: Discussionmentioning

confidence: 99%

De novo loss‐of‐function mutations in X‐linked SMC1A cause severe ID and therapy‐resistant epilepsy in females: expanding the phenotypic spectrum

Jansen¹,

Kleefstra²,

Willemsen³

et al. 2016

Clinical Genetics

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“…Cornelia de Lange syndrome (CdLS) is caused by mutations in genes involved in the cohesin complex [Liu et al, ]. Classic CdLS is due to mutations in NIPBL , while milder or less canonical forms of CdLS have been reported in children with mutations of SMC1A, SMC3A, RAD21 , and HDAC8 [Borck et al, ; Deardorff et al, ; Liu et al, ; Limongelli et al, ; Mannini et al, ; Pié et al, ; Rohatgi et al, ; Chatfield et al, ; Deardorff et al, ; Gervasini et al, ; Hansen et al, ; Mannini et al, ; Parenti et al, ; Goldstein et al, ; Jang et al, ; Lebrun et al, ; Tzschach et al, ]. The phenotype of classic CdLS is well‐known, and includes poor growth, limb deficiencies, synophrys, hearing loss, myopia, congenital heart disease, and renal and genitourinary anomalies.…”

Section: Introductionmentioning

confidence: 99%

“…Until recently, SMC1A ‐associated CdLS was thought to be limited to patients with missense and in‐frame deletions [Mannini et al, ]. However, frameshift mutations in SMC1A have now been reported in children with medically refractory seizures and few craniofacial differences [Goldstein et al, ]. Mosaicism in CdLS due to mutations of the related genes have also been established, which could account for some of the variability in phenotype [Ansari et al, ].…”

Section: Introductionmentioning

confidence: 99%

Novel findings of left ventricular non‐compaction cardiomyopathy, microform cleft lip and poor vision in patient with SMC1A‐associated Cornelia de Lange syndrome

Wenger

Chow

Randle

et al. 2016

American J of Med Genetics Pt A

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Relatively few patients with Cornelia de Lange syndrome (CdLS) due to SMC1A mutation have been reported, limiting understanding of the full extent of the phenotype. Compared to children with classic NIPBL-associated CdLS, patients with SMC1A-associated CdLS have a milder physical phenotype with prominent intellectual disability, high rate of cleft palate and absence of limb reductions. We present a patient with SMC1A-associated CdLS who had typical features including developmental delay, seizure disorder, feeding difficulties, hirsutism, and cleft palate. She also was found to have three novel features: (i) left ventricular non-compaction (LVNC) cardiomyopathy; (ii) microform cleft lip; and (iii) severe hyperopia and astigmatism. These features have implications regarding potential insight into the pathogenesis of the disorder, screening, and medical management. Hypertrophic cardiomyopathy has previously been reported in SMC1A-associated CdLS, but to our knowledge this is the first reported child with LVNC. Previous reports have included children with isolated clefts of the palate without involvement of the lip. When cleft palate alone is associated with a disorder, the underlying pathophysiology for clefting is sometimes secondary due to mechanical blocking of the fusion of the palatal shelves with the developing tongue. The presence of microform cleft lip in this patient suggests that the pathophysiology of clefting in SMC1A is primary rather than secondary. Few studies report ophthalmologic findings specific to SMC1A. Based on these findings, LVNC cardiomyopathy and cleft lip should be considered features of SMC1A-associated CdLS. All patients should receive echocardiogram and undergo thorough ophthalmologic evaluation as part of routine CdLS care. © 2016 Wiley Periodicals, Inc.

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“…SMC1A and SMC3 mutations found in individuals with CdLS were missense mutations or in-frame deletions [Deardorff et al, 2007;Gil-Rodríguez et al, 2015]. Recently, female probands with heterozygous loss-of-function mutations in SMC1A were found in association with seizures and intellectual disability without a clear CdLS phenotype [Goldstein et al, 2015;Lebrun et al, 2015;Jansen et al, 2016]. Therefore, the disease mechanism of SMC1A and SMC3 mutations in CdLS is unlikely to be a mere loss-of-function effect, and a dominant-negative effect is suspected.…”

mentioning

confidence: 99%

Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

Izumi

2016

Mol Syndromol

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Some genetic disorders caused by mutations in genes encoding components of the transcriptional machinery as well as proteins involved in epigenetic modification of the genome share many overlapping features, such as facial dysmorphisms, growth problems and developmental delay/intellectual disability. As a basis for some shared phenotypic characteristics in these syndromes, a similar transcriptome disturbance, characterized by global transcriptional dysregulation, is believed to play a major role. In this review article, a general overview of gene transcription is provided, and the current knowledge of the mechanisms underlying some disorders of transcriptional regulation, such as Rubinstein- Taybi, Coffin-Siris, Cornelia de Lange, and CHOPS syndromes, are discussed.

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Novel SMC1A frameshift mutations in children with developmental delay and epilepsy

Cited by 27 publications

References 28 publications

De novo loss‐of‐function mutations in X‐linked SMC1A cause severe ID and therapy‐resistant epilepsy in females: expanding the phenotypic spectrum

De novo loss‐of‐function mutations in X‐linked SMC1A cause severe ID and therapy‐resistant epilepsy in females: expanding the phenotypic spectrum

Novel findings of left ventricular non‐compaction cardiomyopathy, microform cleft lip and poor vision in patient with SMC1A‐associated Cornelia de Lange syndrome

Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

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