Identification of clinically relevant mosaicism in type I hereditary haemorrhagic telangiectasia

Lee, Nadia Prigoda; Matevski, Donco; Dumitru, Daniela; Piovesan, Beata; Rushlow, Diane; Gallie, Brenda L.

doi:10.1136/jmg.2010.088112

Cited by 15 publications

(12 citation statements)

References 25 publications

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“…Other precedents for somatic mosaicism contributing to the pathogenesis of vascular disorders include the presence of acquired mutations in the endothelial cells of cerebral cavernous malformations (17). Furthermore, somatic mutations in the BMP genes ACVRL1 and ENG have been reported in hereditary hemorrhagic telangiectasia (18)(19)(20)(21). Hereditary hemorrhagic telangiectasia is an endothelial vascular condition, and the disease can manifest when <20% of cells carry the mutation (18).…”

Section: To the Editormentioning

confidence: 99%

Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates SMAD9 Signaling

Drake

Comhair

Erzurum

et al. 2015

Am J Respir Crit Care Med

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Section: To the Editormentioning

confidence: 99%

Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates SMAD9 Signaling

Drake

Comhair

Erzurum

et al. 2015

Am J Respir Crit Care Med

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“…According to our literature review, for 110 non‐cancer genetic disorders there have been one or more sporadic reports of causal mutations inherited from parental mosaicism [Bruttini et al., ; Jones et al., ; Depienne et al., ; Tekin et al., ]. In addition, parental mosaicism has been reported to be the origin of mutations in some families with two or more affected children carrying the same disease‐causing mutation [Lee et al., ; Taioli et al., ].…”

Section: Introductionmentioning

confidence: 99%

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of “ de novo ” SCN1A Mutations in Children with Dravet Syndrome

et al. 2015

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The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered “de novo” by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low‐level mosaicism in parents of families with seemingly “de novo” mutations will allow for better informed genetic counseling.

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“…Mosaic forms have been reported in other autosomal dominant disorders, such as neurofibromatosis 1 and hereditary haemorrhagic telangiectasia (Ruggieri and Huson, 2001;Lee et al, 2011). Some patients with mosaicism have affected children, while others appear unable to pass the mutation on to offspring, suggesting that the mutation can be limited to a part of the soma and thus absent in the germ line.…”

Section: Discussionmentioning

confidence: 99%

CSF1Rmosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

Eichler

Guo

et al. 2016

Brain

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Ã These authors contributed equally to this work.Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G 4 A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.

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Identification of clinically relevant mosaicism in type I hereditary haemorrhagic telangiectasia

Abstract: The results show the importance of investigating patients without prior family history for the presence of mutational mosaicism, as detecting this would enable appropriate genetic screening and targeted medical care for at-risk children of mosaic patients.

Cited by 15 publications

References 25 publications

Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates SMAD9 Signaling

Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates SMAD9 Signaling

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of “ de novo ” SCN1A Mutations in Children with Dravet Syndrome

CSF1Rmosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

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