Novel MLH1 nonsense variant in a patient with suspected Lynch syndrome
HGV datbase
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.3439.
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Beyond CHD7 gene: unveiling genetic diversity in clinically suspected CHARGE syndrome
The Verloes or Hale diagnostic criteria have been applied for diagnosing CHARGE syndrome in suspected patients. This study was conducted to evaluate the diagnostic rate of CHD7 according to these diagnostic criteria in suspected patients and also to investigate other genetic defects in CHD7-negative patients. The clinical findings and the results of genetic testing of CHD7, chromosome microarray, exome sequencing, or genome sequencing of 59 subjects were reviewed. CHD7 pathogenic variants were identified in 78% of 46 subjects who met either the Verloes or Hale diagnostic criteria and in 87% of 38 subjects who met both criteria, whereas no CHD7 variant was detected in 13 subjects who met neither criterion. Among 23 patients without the CHD7 variant, six genetic diseases were identified in 7 patients, including Wolf–Hirschhorn syndrome, 1q21 deletion syndrome, 19q13 microdeletion, and pathogenic variants in PLCB4, TRRAP, and OTX2. Based on these comprehensive analyses, the overall diagnostic rate was 73% for seven different genetic diseases. This study emphasizes the importance of comprehensive clinical and genetic evaluation in patients with clinically suspected CHARGE syndrome, recognizing the overlapping phenotypes in other rare genetic disorders.
Multi-locus inherited neoplasia alleles syndromes in cancer: implications for clinical practice
The popularity of multi-gene testing has identified more families with two or more pathogenic variants (PV) in cancer predisposition genes, also known as ‘MINAS’ (multilocus inherited neoplasia alleles syndromes). They are at risk of suboptimal treatment and management as little on this topic is known. We conducted a systematic review of published MINAS cases within cancer predisposition genes to understand their association with more severe presentations. We analysed 413 MINAS carriers, which included 33 novel cases from the Cancer Genetics Service, National Cancer Centre Singapore. Statistical tests were conducted to assess association between carrier characteristics and the number PV identified. Results suggest that MINAS carriers have more malignancies (31.7% vs 21.5% vs 10.3% %; p < 0.001), a younger median age of first cancer diagnosis (40.0 vs. 44.0 vs. 49.0 years; p < 0.001) and an early onset of cancer (defined as <5% PV-associated cancer risk at age of diagnosis) (24.9% vs 7.7% vs 4.7%; p < 0.001) compared to monoallelic and non-carriers. We also studied the association of clinical characteristics by the dominant or recessive nature of PV harboured, where more dominant-dominant (D-D) carriers reported multiple malignancies (34.0%), compared to dominant-recessive (D-R) (23.9%) and recessive-recessive (R-R) carriers (20%;) (p = 0.051). Our findings suggest that MINAS carriers are prone to more and younger malignancies and the dominant or recessive nature of PV within double carriers can affect clinical presentation. We suggest a framework to guide management based on the dominant or recessive nature of PV within double PV carriers.
The Marchantia polymorpha pangenome reveals ancient mechanisms of plant adaptation to the environment
Plant adaptation to terrestrial life started 450 million years ago and has played a major role in the evolution of life on Earth. The genetic mechanisms allowing this adaptation to a diversity of terrestrial constraints have been mostly studied by focusing on flowering plants. Here, we gathered a collection of 133 accessions of the model bryophyte Marchantia polymorpha and studied its intraspecific diversity using selection signature analyses, a genome–environment association study and a pangenome. We identified adaptive features, such as peroxidases or nucleotide-binding and leucine-rich repeats (NLRs), also observed in flowering plants, likely inherited from the first land plants. The M. polymorpha pangenome also harbors lineage-specific accessory genes absent from seed plants. We conclude that different land plant lineages still share many elements from the genetic toolkit evolved by their most recent common ancestor to adapt to the terrestrial habitat, refined by lineage-specific polymorphisms and gene family evolution.
Homozygous synonymous FAM111A variant underlies an autosomal recessive form of Kenny-Caffey syndrome
FAM111A (family with sequence similarity 111 member A) is a serine protease and removes covalent DNA-protein cross-links during DNA replication. Heterozygous gain-of-function variants in FAM111A cause skeletal dysplasias, such as the perinatal lethal osteocraniostenosis and the milder Kenny-Caffey syndrome (KCS). We report two siblings born to consanguineous parents with dysmorphic craniofacial features, postnatal growth retardation, ophthalmologic manifestations, hair and nail anomalies, and skeletal abnormalities such as thickened cortex and stenosis of the medullary cavity of the long bones suggestive of KCS. Using exome sequencing, a homozygous synonymous FAM111A variant, NM_001312909.2:c.81 G > A; p.Pro27=, that affects the last base of the exon and is predicted to alter FAM111A pre-mRNA splicing, was identified in both siblings. We identified aberrantly spliced FAM111A transcripts, reduced FAM111A mRNA levels, and near-complete absence of FAM111A protein in fibroblasts of both patients. After treatment of patient and control fibroblasts with different concentrations of camptothecin that induces covalent DNA-protein cross-links, we observed a tendency towards a reduced proportion of metabolically active cells in patient compared to control fibroblasts. However, under these culture conditions, we did not find consistent and statistically significant differences in cell cycle progression and apoptotic cell death between patient and control cells. Our findings show that FAM111A deficiency underlies an autosomal recessive form of FAM111A-related KCS. Based on our results and published data, we hypothesize that loss of FAM111A and FAM111A protease hyperactivity, as observed for gain-of-function patient-variant proteins, may converge on a similar pathomechanism underlying skeletal dysplasias.
Wilson disease (novel ATP7B variants) with concomitant FLNC-related cardiomyopathy
We report a case of Wilson disease (WD) with dilated cardiomyopathy in which whole-genome sequencing (WGS) revealed the rare co-occurrence of two novel compound heterozygous ATP7B pathogenic variants (NM_001005918.3:c.2250del/p.N751Tfs*9 and c.3496C>T/p.L1166F) and a known FLNC pathogenic variant. Our results highlight the usefulness of WGS, even in the diagnosis of well-characterized genetic diseases such as WD.
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