A Prenatal Presentation of Severe Microcephaly and Brain Anomalies in a Patient With Novel Compound Heterozygous Mutations in the STIL Gene Found Postnatally With Exome Analysis

Bennett, Harvey; Presti, Amy; Adams, Darius; Rios, Jose; Benito, Carlos; Cohen, Daniel

doi:10.1016/j.pediatrneurol.2014.05.023

Cited by 9 publications

(7 citation statements)

References 3 publications

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“…However, STIL mutations are likely a rare cause of HPE as Karkera et al (2002) had previously screened 83 patients representing the full severity spectrum of HPE without identifying STIL mutations. While our manuscript was in preparation, Bennett and coworkers reported a child with compound heterozygous STIL mutations and a complex brain malformation that was reminiscent of HPE in the fetus but postnatally interpreted as representing large symmetric bilateral schizencephaly or hydranencephaly with underlying migrational abnormalities (Bennett et al 2014). On review of the published MRI we believe this patient has HPE, further confirming our findings.…”

Section: Discussionmentioning

confidence: 98%

STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

et al. 2014

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Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly.

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Section: Discussionmentioning

confidence: 98%

STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

et al. 2014

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“…4 ; Table 1 ), and besides MC, other brain abnormalities including a simplified gyral pattern, reduction of the white matter, abnormal corpus callosum, and lobar HPE were often seen [Kumar et al, 2009;Bennett et al, 2014;Kakar et al, 2015;Mouden et al, 2015]. Fetal CNS developmental abnormalities caused by compound heterozygous STIL mutations have been described in a single previous study in which fetal MC was observed at the 20th gestational week by ultrasound imaging [Bennett et al, 2014]. In this case, MRI imaging performed at the 31st week of gestation revealed severe MC and anomalies consistent with HPE.…”

Section: Discussionmentioning

confidence: 99%

Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening

Cristofoli

Keersmaecker²,

Catte³

et al. 2017

Mol Syndromol

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STIL (SCL/TAL1 interrupting locus) is a core component of the centriole duplication process. <i>STIL</i> mutations have been associated with both autosomal recessive primary microcephaly (MCPH) and holoprosencephaly. In this report, we describe a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum. Whole exome sequencing allowed us to identify novel compound heterozygous mutations in <i>STIL.</i> The mutations lie, respectively, in the CPAP/CENPJ and the hsSAS6 interacting domains of STIL. M-phase synchronized amniocytes from both affected fetuses did not display an aberrant number of centrioles, as shown previously for either STIL-depleted or overexpressing cells. However, we observed an elongation of at least 1 centriole for each duplicated centrosome. These preliminary results may point to a novel mechanism causing MCPH and embryonic lethality in humans.

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“…So far, eight mutations in STIL have been described in 37 patients all showing severe microcephaly (−4 to −10 S.D.). Five mutations are splice 42 , 43 , deletion, nonsense 43 , or duplication 44 that predict the production of truncated proteins, while three mutations are missense substitutions 44 – 46 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

STIL balancing primary microcephaly and cancer

Patwardhan¹,

Mani²,

Passemard³

et al. 2018

Cell Death Dis

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Cell division and differentiation are two fundamental physiological processes that need to be tightly balanced to achieve harmonious development of an organ or a tissue without jeopardizing its homeostasis. The role played by the centriolar protein STIL is highly illustrative of this balance at different stages of life as deregulation of the human STIL gene expression has been associated with either insufficient brain development (primary microcephaly) or cancer, two conditions resulting from perturbations in cell cycle and chromosomal segregation. This review describes the recent advances on STIL functions in the control of centriole duplication and mitotic spindle integrity, and discusses how pathological perturbations of its finely tuned expression result in chromosomal instability in both embryonic and postnatal situations, highlighting the concept that common key factors are involved in developmental steps and tissue homeostasis.

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A Prenatal Presentation of Severe Microcephaly and Brain Anomalies in a Patient With Novel Compound Heterozygous Mutations in the STIL Gene Found Postnatally With Exome Analysis

Cited by 9 publications

References 3 publications

STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening

STIL balancing primary microcephaly and cancer

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