STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

Kakar, Naseebullah; Ahmad, Jamil; Morris-Rosendahl, Deborah J.; Altmüller, Janine; Friedrich, Katrin; Barbi, Gotthold; Nürnberg, Peter; Kubisch, Christian; Dobyns, William B.; Borck, Guntram

doi:10.1007/s00439-014-1487-4

Cited by 31 publications

(28 citation statements)

References 23 publications

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“…Unfortunately, no material was present to perform genetic testing retrospectively. Despite this, the phenotype variability observed between individuals with the same STIL mutations [e.g., Kakar et al, 2015;Mouden et al, 2015] ( Table 1 ) allows us to hypothesize that more severe brain malformations may have happened in the previous pregnancies.…”

Section: Discussionmentioning

confidence: 96%

“…Subsequently, several other families have been described (overview in Fig. 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].…”

Section: Discussionmentioning

confidence: 99%

“…Morever, in recent years, it has become clear that MCPH has both a genetic and clinical overlap with other neurodevelopmental disorders, such as Seckel syndrome, Meier-Gorlin syndrome, and microcephalic primordial dwarfism. For instance, biallelic defects in the genes CPAP/CENPJ and CEP152 have been associated to both MCPH and Seckel syndrome [Bond et al, 2005;AlDosari et al, 2010;Guernsey et al, 2010;Kalay et al, 2011], CENPE mutations to MCPH and microcephalic primordial dwarfism [Mirzaa et al, 2014], while STIL mutations have been found both in patients with MCPH and holoprosencephaly (HPE) [Kumar et al, 2009;Kakar et al, 2015;Mouden et al, 2015], leading to the conclusion that this group of disorders may be considered as a clinical continuum rather than individual entities [Barbelanne and Tsang, 2014;Morris-Rosendahl and Kaindl, 2015].…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Cristofoli

Keersmaecker²,

Catte³

et al. 2017

Mol Syndromol

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“…Heterozygous mutations in the minor genes, GLI2, PTCH1, DISP1, FOXH1, NODAL, TDGF1, CDON, GAS1, DLL1 and FGF8, have been identified with a lower frequency (2,7). Recently, two recessive inheritance cases of HPE have been described, implicating mutations in the gene STIL (Table 1) (8,9). Importantly, these genes are all involved in signalling pathways implicated in brain development (4,(9)(10)(11)(12)(13)(14)(15)(16) and alteration of SHH signalling appears to be the most common cause of HPE (17).…”

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confidence: 99%

Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

et al. 2016

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Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling.

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“…Most recently, post-natal WES revealed two novel STIL mutations in a compound heterozygous constellation in a foetus with microcephaly and a structural brain anomaly consistent with holoprosencephaly [70]. Subsequently, WES from a single patient from an extended consanguineous family revealed another recessive STIL splice mutation in patients with microcephaly and lobar holoprosencephaly [71], thus confirming STIL mutation as a cause of holoprosencephaly.…”

Section: Stil and Holoprosencephalymentioning

confidence: 89%

What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH)

Morris-Rosendahl

Kaindl

2015

Molecular and Cellular Probes

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The impact that next-generation sequencing technology (NGS) is having on many aspects of molecular and cell biology, is becoming increasingly apparent. One of the the most noticeable outcomes of the new technology in human genetics, has been the accelerated rate of identification of disease-causing genes. Especially for rare, heterogeneous disorders, such as autosomal recessive primary microcephaly (MCPH), the handful of genes previously known to harbour disease-causing mutations, has grown at an unprecedented rate within a few years. Knowledge of new genes mutated in MCPH over the last four years has contributed to our understanding of the disorder at both the clinical and cellular levels. The functions of MCPH proteins such as WDR62, CASC5, PHC1, CDK6, CENP-E, CENP-F, CEP63, ZNF335, PLK4 and TUBGPC, have been added to the complex network of critical cellular processes known to be involved in brain growth and size. In addition to the importance of mitotic spindle assembly and structure, centrosome and centriole function and DNA repair and damage response, new mechanisms involving kinetochore-associated proteins and chromatin remodelling complexes have been elucidated. Two of the major contributions to our clinical knowledge are the realisation that primary microcephaly caused by mutations in genes at the MCPH loci is seldom an isolated clinical feature and is often accompanied either by additional cortical malformations or primordial dwarfism. Gene-phenotype correlations are being revisited, with a new dimension of locus heterogeneity and phenotypic variablity being revealed.

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STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

Cited by 31 publications

References 23 publications

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

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

Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH)

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