Bohring‐Opitz syndrome caused by an <i>ASXL1</i> mutation inherited from a germline mosaic mother

Bedoukian, Emma; Copenheaver, Deborah; Bale, Sherri J.; Deardorff, Matthew A.

doi:10.1002/ajmg.a.38686

Cited by 18 publications

(19 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By 5 years of age, she was nonverbal, nonmobile, and unable to use her hands. This patient was previously reported at 3 years of age as the first description of BOPS inherited from an unaffected, germ line mosaic parent (Bedoukian et al, 2018).…”

Section: Case Reportsmentioning

confidence: 81%

Understanding the phenotypic spectrum of ASXL‐related disease: Ten cases and a review of the literature

Cuddapah

Dubbs

Adang

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring–Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi–Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge–Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL‐related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

show abstract

Section: Case Reportsmentioning

confidence: 81%

Understanding the phenotypic spectrum of ASXL‐related disease: Ten cases and a review of the literature

Cuddapah

Dubbs

Adang

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…Nonetheless, several factors must be taken into account in the filtering process of trio exome data. Dominant disorders may exhibit incomplete penetrance or variable expressivity, alleles may be subject to imprinting depending on parent of origin (Eggermann et al, 2015;Soellner et al, 2017), and a parent may have mosaicism of a pathogenic variant (Bedoukian, Copenheaver, Bale, & Deardorff, 2018;Rabin, Millan, Cabrera-Luque, & Pappas, 2018;Rump et al, 2013;van den Akker, Pasmooij, Meijer, Scheffer, & Jonkman, 2015). Moreover, in disorders with X-linked inheritance, nonrandom skewed X chromosome inactivation may lead to a phenotype in a female offspring whereas the transmitting female (mother) would be unaffected (Van den Veyver, 2001).…”

mentioning

confidence: 99%

Grandparental genotyping enhances exome variant interpretation

Daum

Mor‐Shaked

Ta‐Shma

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband‐only sequencing, mainly due to the rapid identification of de novo disease‐causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X‐inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X‐inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.

show abstract

“…A driver mutation is by definition a genetic change that gives an advantage to the cell. The advantage enables the cell to grow and proliferate better than other cells, which is a hallmark in cancer AA, amino acid; AD, autosomal dominant; ASXL1 , ASXL transcriptional regulator 1; BRAF , B-Raf proto-oncogene, serine/threonine kinase; CBL , Cbl proto-oncogene; COSMIC, Catalogue of Somatic Mutations in Cancer; DNMT3A , DNA methyltransferase 3 alpha; FGFR3 , fibroblast growth factor receptor 3; IDH2 , isocitrate dehydrogenase (NADP(+)) 2;; LADD, Lacrimo-auriculo-dento-digital; KRAS , KRAS proto-oncogene, GTPase; PTPN11 , protein tyrosine phosphatase non-receptor type 11 ▲ Evidence of somatic mosaicism involving the germline reported by Erickson [ 39 ] or Bedoukian et al[ 30 ] ∆ Genes involved in stem cell and/or cell population proliferation ► Variant reported to affect or probably affect function based on Leiden Open Variation Database (LOVD; hg19/GRCh37) version 3.0 [ 40 ] *Genes with evidence of mosaicism that overlap with the list of 156 hematopoietic genes provided by Jaiswal et al [ 13 ] in their Additional file 1 : Table S2 ( n = 7) **A gene shows good evidence of mosaicism when at least two alleles show signs of somatic origin (allelic imbalance) ***Rare disease- and/or cancer-related known pathogenic or likely pathogenic variants (in ClinVar and/or COSMIC)…”

Section: Resultsmentioning

confidence: 99%

Driving mosaicism: somatic variants in reference population databases and effect on variant interpretation in rare genetic disease

et al. 2021

View full text Add to dashboard Cite

Background Genetic variation databases provide invaluable information on the presence and frequency of genetic variants in the ‘untargeted’ human population, aggregated with the primary goal to facilitate the interpretation of clinically important variants. The presence of somatic variants in such databases can affect variant assessment in undiagnosed rare disease (RD) patients. Previously, the impact of somatic mosaicism was only considered in relation to two Mendelian disease-associated genes. Here, we expand the analyses to identify additional mosaicism-prone genes in blood-derived reference population databases. Results To identify additional mosaicism-prone genes relevant to RDs, we focused on known/previously established ClinVar pathogenic and likely pathogenic single-nucleotide variants, residing in genes associated with early onset, severe autosomal dominant diseases. We asked whether any of these variants are present in a higher-than-expected frequency in the reference population databases and whether there is evidence of somatic origin (i.e., allelic imbalance) rather than germline heterozygosity (~ half of the reads supporting alternative allele). The mosaicism-prone genes identified were further categorized according to the processes they are involved in. Beyond the previously reported ASXL1 and DNMT3A, we identified 7 additional autosomal dominant RD-associated genes with known pathogenic single-nucleotide variants present in the reference population databases and good evidence of allelic imbalance: BRAF, CBL, FGFR3, IDH2, KRAS, PTPN11 and SETBP1. From this group of 9 genes, the majority (n = 7) was important for hematopoiesis. In addition, 4 of these genes were involved in cell proliferation. Further assessment of the known 156 hematopoietic genes led to identification of 48 genes (21 not yet associated with RDs) with at least some evidence of mosaicism detectable in reference population databases. Conclusions These results stress the importance of considering genes involved in hematopoiesis and cell proliferation when interpreting the presence and frequency of genetic variants in blood-derived reference population databases, both public and private. This is especially important when considering new variants of uncertain significance in known hematopoietic/cell proliferation RD genes and future novel gene–disease associations involving this class of genes.

show abstract

Bohring‐Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother

Cited by 18 publications

References 16 publications

Understanding the phenotypic spectrum of ASXL‐related disease: Ten cases and a review of the literature

Understanding the phenotypic spectrum of ASXL‐related disease: Ten cases and a review of the literature

Grandparental genotyping enhances exome variant interpretation

Driving mosaicism: somatic variants in reference population databases and effect on variant interpretation in rare genetic disease

Contact Info

Product

Resources

About