Transformer2 proteins (Tra2α and Tra2β) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to ...associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder.
A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells.
All variants clustered in the 5′ part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1.
Predicted loss-of-function variants clustered in the 5′ portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein.
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Background and purpose
Muscular A‐type lamin‐interacting protein (MLIP) is most abundantly expressed in cardiac and skeletal muscle. In vitro and animal studies have shown its regulatory role in ...myoblast differentiation and in organization of myonuclear positioning in skeletal muscle, as well as in cardiomyocyte adaptation and cardiomyopathy. We report the association of biallelic truncating variation in the MLIP gene with human disease in five individuals from two unrelated pedigrees.
Methods
Clinical evaluation and exome sequencing were performed in two unrelated families with elevated creatine kinase level.
Results
Family 1. A 6‐year‐old girl born to consanguineous parents of Arab‐Muslim origin presented with myalgia, early fatigue after mild‐to‐moderate physical exertion, and elevated creatine kinase levels up to 16,000 U/L. Exome sequencing revealed a novel homozygous nonsense variant, c.2530C>T; p.Arg844Ter, in the MLIP gene. Family 2. Three individuals from two distantly related families of Old Order Amish ancestry presented with elevated creatine kinase levels, one of whom also presented with abnormal electrocardiography results. On exome sequencing, all showed homozygosity for a novel nonsense MLIP variant c.1825A>T; p.Lys609Ter. Another individual from this pedigree, who had sinus arrhythmia and for whom creatine kinase level was not available, was also homozygous for this variant.
Conclusions
Our findings suggest that biallelic truncating variants in MLIP result in myopathy characterized by hyperCKemia. Moreover, these cases of MLIP‐related disease may indicate that at least in some instances this condition is associated with muscle decompensation and fatigability during low‐to‐moderate intensity muscle exertion as well as possible cardiac involvement.
This study reports the association of biallelic truncating variants in the muscular A‐type lamin‐interacting protein (MLIP) gene with human disease in five individuals from two unrelated pedigrees. The reported MLIP‐associated disorder causes abnormally elevated creatine kinase levels and may also include exertion‐induced myalgia, muscle decompensation and fatigability during low‐to‐moderate muscle exertion, and cardiac involvement.
Purpose
While the spectrum of germline mutations in
BRCA1/2
genes in the Israeli Jewish population has been extensively studied, there is a paucity of data pertaining to Israeli Arab high-risk cases.
...Methods
Consecutive Israeli Arab breast and/or ovarian cancer patients were recruited using an ethically approved protocol from January 2012 to February 2019. All ovarian cancer cases were referred for
BRCA
genotyping. Breast cancer patients were offered
BRCA
sequencing and deletion/duplication analysis after genetic counseling, if the calculated risk for carrying a
BRCA
mutation by risk prediction algorithms was ≥10%.
Results
Overall, 188 patients participated; 150 breast cancer cases (median age at diagnosis: 40 years, range 22–67) and 38 had ovarian cancer (median age at diagnosis: 52.5 years, range 26–79). Of genotyped cases, 18 (10%) carried one of 12 pathogenic or likely-pathogenic variants, 12 in
BRCA1,
6 in
BRCA2
. Only one was a rearrangement. Three variants recurred in more than one case; one was detected in five seemingly unrelated families. The detection rate for all breast cancer cases was 4%, 5% in bilateral breast cancer cases and 3% if breast cancer was diagnosed < 40 years. Of patients with ovarian cancer, 12/38 (32%) were carriers; the detection rate reached 75% (3/4) among patients diagnosed with both breast and ovarian cancer.
Conclusions
The overall yield of comprehensive
BRCA1/2
testing in high-risk Israeli Arab individuals is low in breast cancer patients, and much higher in ovarian cancer patients. These results may guide optimal cancer susceptibility testing strategy in the Arab–Israeli population.
ABSTRACT
Objective
Laboratories performing prenatal exome sequencing (ES) frequently limit analysis to predetermined gene lists. We used a diagnostic postnatal ES cohort to assess how many of the ...genes diagnosed are not included in a number of select fixed lists used for prenatal diagnosis.
Methods
Of 601 postnatal ES tests, pathogenic variants related to neurodevelopmental disorders were detected in 138 probands. We evaluated if causative genes were present in the following: (1) Developmental Disorders Genotype–Phenotype database list, (2) a commercial laboratory list for prenatal ES, (3) the PanelApp fetal anomalies panel, and (4) a published list used for prenatal diagnosis by ES (Prenatal Assessment of Genomes and Exomes study).
Results
The percentages of cases where the diagnosed gene was not included in the selected four lists were; 11.6%, 17.24%, 23.2%, and 10.9%, respectively. In 13/138 (9.4%) cases, the causative gene was not included in any of the lists; in 4/13 (∼30%) cases noninclusion was explained by a relatively recent discovery of gene–phenotype association.
Conclusions
A significant number of genes related to neurocognitive phenotypes are not included in some of the lists used for prenatal ES data interpretation. These are not only genes related to recently discovered disorders, but also genes with well‐established gene–phenotype.
Key Points
What's already known about this topic?
Laboratories performing prenatal exome sequencing (ES) frequently limit analysis to predetermined gene lists.
We used a postnatal ES cohort to assess how many of the genes diagnosed in this cohort are not included in selected fixed lists.
What does this study add?
A significant number of genes related to neurocognitive phenotypes are not included in curated lists.
This results from noninclusion of recently discovered disorders, as well as disorders with well‐established gene–phenotype associations.
Incipient sympatric speciation in blind mole rat, Spalax galili, in Israel, caused by sharp ecological divergence of abutting chalk–basalt ecologies, has been proposed previously based on ...mitochondrial and whole-genome nuclear DNA. Here, we present new evidence, including transcriptome, DNA editing, microRNA, and codon usage, substantiating earlier evidence for adaptive divergence in the abutting chalk and basalt populations. Genetic divergence, based on the previous and new evidence, is ongoing despite restricted gene flow between the two populations. The principal component analysis, neighbor-joining tree, and genetic structure analysis of the transcriptome clearly show the clustered divergent two mole rat populations. Gene-expression level analysis indicates that the population transcriptome divergence is displayed not only by soil divergence but also by sex. Gene ontology enrichment of the differentially expressed genes from the two abutting soil populations highlights reproductive isolation. Alternative splicing variation of the two abutting soil populations displays two distinct splicing patterns. L-shaped F
ST distribution indicates that the two populations have undergone divergence with gene flow. Transcriptome divergent genes highlight neurogenetics and nutrition characterizing the chalk population, and energetics, metabolism, musculature, and sensory perception characterizing the abutting basalt population. Remarkably, microRNAs also display divergence between the two populations. The GC content is significantly higher in chalk than in basalt, and stress-response genes mostly prefer nonoptimal codons. The multiple lines of evidence of ecological–genomic and genetic divergence highlight that natural selection overrules the gene flow between the two abutting populations, substantiating the sharp ecological chalk–basalt divergence driving sympatric speciation.
POLR3A encodes the largest subunit of the DNA‐dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non‐coding RNAs. ...POLR3A‐related disorders include variable phenotypes. The genotype–phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46–55) had similar clinical features of early childhood‐onset hypodontia and adolescent‐onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis‐acting intronic splicing‐altering variants, c.1909 + 22G > A and c.3337–11 T > C. The two healthy siblings had wild‐type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann‐Rautenstrauch syndrome, a severe progeroid POLR3A‐associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype–phenotype correlation in POLR3A‐related disorders.
Early-onset epileptic encephalopathy (EOEE) is a severe convulsive disorder with a poor developmental prognosis. Although it has been associated with mutations in a number of genes, the fact that ...there is a large proportion of patients who remain undiagnosed suggests that there are many more still-unknown genetic causes of EOEE. Achieving a genetic diagnosis is important for understanding the biological basis of the disease, with its implications for treatment and family planning.
Whole-exome sequencing was performed in a family of Ashkenazi Jewish origin in which a male infant was diagnosed with EOEE. There was no family history of a similar neurologic disease. The patient had extreme hypotonia, neonatal hypothermia, choreiform movements, and vision impairment in addition to the convulsive disorder.
A de novo heterozygous missense mutation, c.1003A > C, p.Asn335His, was identified in a conserved domain of GABRA2. GABRA2 encodes the α2 subunit of the GABAA receptor.
In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABAA receptor (GABRB1, GABRA1, GABRG2, GABRB3) with autosomal dominant epileptic disorders, we conclude that a de novo mutation in GABRA2 is likely to cause autosomal dominant EOEE accompanied by a movement disorder and vision impairment.
•Mutations in GABAA receptors are associated with early onset epileptic encephalopathy.•GABRA2 encodes the α2 subunit of the GABAA receptor which is an important component of the gamma aminobutyric acid system.•We report that a de novo mutation in GABRA2 is likely to cause autosomal dominant early onset epileptic encephalopathy.•GABRA2 mutations have not been previously reported in association with human disease.
POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene ...have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1–6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.
In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short ...stature and hearing loss. Recently, mutations in AMMECR1 were reported in two maternal half-brothers, presenting with nephrocalcinosis, midface hypoplasia and, in one of the siblings, deafness and elliptocytosis. AMMECR1 gene is localized in the critical region of contiguous deletion syndrome on Xq22.3 implicated in Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME complex). Interestingly, alternative splicing of exon 2, the same exon harboring the truncating mutation, was observed in the proband and in his unaffected mother. Alternative splicing of this exon is predicted to lead to an in-frame deletion. We provide further evidence that mutated AMMECR1 gene is responsible for this clinically recognizable X-linked condition with variable expressivity.
•Family with X-linked recessive syndrome caused by mutated AMMECR1•Clinical features include elliptocytosis, midface hypoplasia, short stature, hearing loss.•AMMECR1 is localized in the critical region of contiguous deletion syndrome on Xq22.3.•Region implicated in Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis
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