Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants

Frisk, Sofia; Wachtmeister, Alexandra; Laurell, Tobias; Wedell, Anna; Jäntti, Nina; Malmgren, Helena; Lagerstedt‐Robinson, Kristina; Tesi, Bianca; Taylan, Fulya

doi:10.1002/mgg3.1880

Cited by 12 publications

(13 citation statements)

References 58 publications

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“…While our methods theoretically allowed for finer detectability than in most similar studies, we did not identify a larger proportion of parental mosaics. The proportion of 3% is at the lower limit of previous studies on pathogenic DNV 7 . It is uncertain whether pathogenic variants of certain specific diseases could be associated with larger proportions of parental mosaics and what the underlying biological mechanism could be.…”

Section: Discussionmentioning

confidence: 68%

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Assessment of parental mosaicism rates in neurodevelopmental disorders caused by apparent de novo pathogenic variants using deep sequencing

Lecoquierre,

Cassinari,

Drouot

et al. 2024

Sci Rep

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While de novo variants (DNV) are overall at low risk of recurrence in subsequent pregnancies, a subset is at high risk due to parental mosaicism. Accurately identifying cases of parental mosaicism is therefore important for genetic counseling in clinical care. Some studies have investigated the rate of parental mosaics, but most were either limited by the sensitivity of the techniques (i.e. exome or genome sequencing), or focused on specific types of disease such as epileptic syndromes. This study aimed to determine the proportion of parental mosaicism among the DNV causing neurodevelopmental disorders (NDDs) in a series not enriched in epilepsy syndromes. We collected 189 patients with NDD-associated DNV. We applied a smMIP enrichment method and sequenced parental blood DNA samples to an average depth of 7000x. Power simulation indicated that mosaicism with an allelic fraction of 0.5% would have been detected for 87% of positions with 90% power. We observed seven parental mosaic variants (3.7% of families), of which four (2.1% of families) had an allelic fraction of less than 1%. In total, our study identifies a relatively low proportion of parental mosaicism in NDD-associated DNVs and raises the question of a biological mechanism behind the higher rates of parental mosaicism detected in other studies, particularly those focusing on epileptic syndromes.

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Section: Discussionmentioning

confidence: 68%

“…Several studies aimed to assess the prevalence of parental mosaicism in presumed DNVs 7 . Some of them used large exome datasets of child-parents trios, obtained from blood samples, and with sequencing depths of coverage adapted to the detection of germline variants.…”

Section: Introductionmentioning

confidence: 99%

Assessment of parental mosaicism rates in neurodevelopmental disorders caused by apparent de novo pathogenic variants using deep sequencing

Lecoquierre,

Cassinari,

Drouot

et al. 2024

Sci Rep

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“…2). Furthermore, many cases of Kleefstra syndrome caused by nonsense, frameshift, and splice-site changes within this region have been reported [Willemsen et al, 2012;Bock et al, 2016;Huang et al, 2021;Frisk et al, 2022]. Additionally, Fear et al [2022] demonstrated that haplozygous cells of the truncated EHMT1 gene, a premature termination codon in the SET domain, confer features of Kleefstra syndrome.…”

Section: Discussionmentioning

confidence: 99%

Reanalysis of Chromosomal Microarray Data Using a Smaller Copy Number Variant Call Threshold Identifies Four Cases with Heterozygous Multiexon Deletions of ARID1B, EHMT1, and FOXP1 Genes

Kubota¹,

Takeda²,

Kobayashi³

et al. 2023

Mol Syndromol

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Introduction: Chromosomal microarray (CMA) is a highly accurate and established method for detecting copy number variations (CNVs) in clinical genetic testing. CNVs are important etiological factors for disorders such as intellectual disability, developmental delay, and multiple congenital anomalies. Recently developed analytical methods have facilitated the identification of smaller CNVs. Therefore, reanalyzing CMA data using a smaller CNV calling threshold may yield useful information. However, this method was left to the discretion of each institution. Methods: We reanalyzed the CMA data of 131 patients using a smaller CNV call threshold: 50 kb 50 probes for gain and 25 kb 25 probes for loss. We interpreted the reanalyzed CNVs based on the most recently available information. In the reanalysis, we filtered the data using the Clinical Genome Resource dosage sensitivity gene list as an index to quickly and efficiently check morbid genes. Results: The number of copy number loss was approximately 20 times greater, and copy number gain was approximately three times greater compared to those in the previous analysis. We detected new likely pathogenic CNVs in four participants: a 236.5 kb loss within ARID1B, a 50.6 kb loss including EHMT1, a 46.5 kb loss including EHMT1, and an 89.1 kb loss within the FOXP1 gene. Conclusion: The method employed in this study is simple and effective for CMA data reanalysis using a smaller CNV call threshold. Thus, this method is efficient for both ongoing and repeated analyses. This study may stimulate further discussion of reanalysis methodology in clinical laboratories.

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“…In order to establish the prevalence of mosaicism in the parents of patients with intellectual disability syndromes caused by novel variants, Frisk et al ( 2022 ) performed ddPCR on DNA extracted from the blood of 43 trios and the sperm of 31 fathers. They detected low‐level mosaicism (EHMT1, c.2986C>T) only in the sperm‐derived DNA (1.1%) but not in blood.…”

Section: Discussionmentioning

confidence: 99%

Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

Xie

Luo

Zhong

et al. 2023

Molec Gen & Gen Med

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Background Emery–Dreifuss muscular dystrophy (EDMD2) is a rare form of muscular dystrophy that is inherited as an autosomal dominant trait. In some patients, it is inherited from parental mosaicism, and this increases the recurrence risk significantly. The presence of mosaicism is underestimated due to the limitations of genetic testing and the difficulty in obtaining samples. Methods A peripheral blood sample from a 9‐year‐old girl with EDMD2 was analyzed by enhanced whole exome sequencing (WES). Sanger sequencing in her unaffected parents and younger sister was performed for validation. In the mother, ultra‐deep sequencing and droplet digital PCR (ddPCR) in multiple samples (blood, urine, saliva, oral epithelium, and nail clippings) were performed in order to identify the suspected mosaicism of the variant. Results WES revealed a heterozygous mutation (LMNA, c.1622G>A) in the proband. Sanger sequencing of the mother suggested the presence of mosaicism. The ratio of mosaic mutation was confirmed in different samples by ultra‐deep sequencing and ddPCR (19.98%–28.61% and 17.94%–28.33%, respectively). This inferred that the mosaic mutation may have occurred early during embryonic development and that the mother had gonosomal mosaicism. Conclusion We described a case of EDMD2 caused by maternal gonosomal mosaicism which was confirmed by using ultra‐deep sequencing and ddPCR. This study illustrates the importance of a systematic and comprehensive screening of parental mosaicism with more sensitive approaches and the use of multiple tissue samples.

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Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants

Cited by 12 publications

References 58 publications

Assessment of parental mosaicism rates in neurodevelopmental disorders caused by apparent de novo pathogenic variants using deep sequencing

Assessment of parental mosaicism rates in neurodevelopmental disorders caused by apparent de novo pathogenic variants using deep sequencing

Reanalysis of Chromosomal Microarray Data Using a Smaller Copy Number Variant Call Threshold Identifies Four Cases with Heterozygous Multiexon Deletions of ARID1B, EHMT1, and FOXP1 Genes

Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

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