Disease Progression and Clinical Outcomes in Telomere Biology Disorders

Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR) or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs [144 male, 86.6% known genotype, median age at diagnosis 19.4 years (0-71.6)], enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up [median follow-up 5.2 years (0-36.7)]. Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure, severe liver disease and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival of 52.8 years [95% confidence interval (CI) 45.5-57.6] and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better overall survival was present in AD versus AR/XLR/TINF2 disease (p<0.01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines, and risk stratification in patients with DC/TBDs. clinicaltrials.gov NCT00027274

PIEZO1 Mutation May Determine Early Onset of Clinical Manifestation of Anemia of Myelodysplastic Syndromes

BACKGROUND: Anemia is the most frequent cytopenia in myelodysplastic syndromes (MDS), neoplastic diseases characterized by ineffective hematopoiesis and bone marrow dysplasia. MDS usually affect elderly individuals (median age in Italy 74 years), and quite rarely concern younger patients. It is of increasing interest to verify whether "young", not therapy-related MDS patients carry germline (GM) predisposition, in order to optimize therapeutic and transplant choices. The best approach is to perform Whole Exome Sequencing (WES) instead of targeted next-generation sequencing (t-NGS) panel in cases in which MDS patients have no syndromic signs or any indicative sign of predisposing alterations. AIM: We considered a cohort of 21 consecutive MDS cases with age at diagnosis < 60 years and anemia, referred to our MDS Unit for a second opinion. METHODS: After bone marrow (BM) re-evaluation and morphological confirmation of dysplasia compatible with MDS, we screened the 21 MDS patients by WES on BM-DNA or peripheral blood DNA (PB-DNA). For DNA sequencing, DNA libraries were sequenced using the NextSeq 550 Illumina System. Variant calling was carried out using GATK caller. T-NGS myeloid panel was in some cases applied to confirm somatic nature of mutations. Samples of 5/21 MDS patients and their relatives were further analyzed after WES by applying high-coverage t-NGS 86-gene custom panel for hereditary anemias on PB-DNA. WES of DNA extracted from saliva (S-DNA) samples was performed to provide a GM confirmation. In order to confirm pathogenic role in red blood cell (RBC) membrane defects of identified variants, we also performed the ektacytometry analysis that evaluates the erythrocyte deformability and the hydration status by subjecting them to an increasing osmotic gradient with constant shear stress. RESULTS: Five of 21 MDS cases (23.8%) with symptomatic anemia (3 MDS-MLD, 1 MDS-SLD, 1 MDS with isolated del5q) were identified as carriers of variants suspected responsible of RBC membrane defects in both BM/PB-DNA and S-DNA samples, where no other germline myeloid predisposing alterations were demonstrated. MDS-associated somatic variants were present in 4/5 patients (KRAS, TET2, CBL, SRSF2, U2AF1, IDH2, with VAF >25 %). High coverage t-NGS analysis confirmed the presence of a heterozygous rare missense variant in PIEZO1 in probands 1 and 5; a heterozygous rare missense variant in PIEZO1 and ANK1 in proband 2; a heterozygous rare missense variant in PIEZO1 and SPTA1 in proband 3; a complex mode of inheritance in proband 4 with causative variants in G6PD, KCCN4, SPTB, and ABCB6 genes. PIEZO1 or KCNN4 gene variants result in erythrocyte dehydration and determine dehydrated hereditary stomatocytosis (DHS). Ektacytometry analysis showed a significant difference in the osmolarity curve of these patients, confirming the pathogenic role of the variants identified. Among these MDS suspected cases, only proband 4 was diagnostically re-categorized because of lack of acquired recurrent somatic mutations and presence of multiple alterations in erythroid genes causing dysplasia of erythroid precursors, masquerading as MDS. None of the patients presented a history of unexplained anemia before the onset of MDS, consistent with what shown for DHS1 patients with well-compensated hemolysis. Inheritance pattern of the identified variants according the study of the families confirmed the segregation of the pathogenic variants. CONCLUSION: Onset of de novo MDS in unusually young age should always prompt investigation of predisposing conditions. We suggest here that co-existence of inherited RBC membrane defects with MDS may determine earlier clinical manifestation of the clonal disease. Hereditary anemias, in particular xerocytosis, may mimic MDS morphology. In our study, among the 5 "young" MDS with concomitant inherited RBC membrane defect, one case did not finally confirm MDS diagnosis by karyotype or NGS myeloid mutation analysis. This case fulfilled the diagnostic criteria for combined hereditary hemolytic anemia: DHS2, G6PD deficiency, spherocytosis, familial pseudohyperkalemia 2, with multi-locus mode of inheritance that justifies the clinical condition (splenomegaly, hemolytic crisis, ascites). Addition of genetic testing for hereditary anemias beside assessment of germline predisposing variants may allow a more precise diagnosis in controversial cases of "young" MDS. Disclosures Sanna: Janssen: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy. Iolascon: Celgene: Other: Advisory Board; Bluebird Bio: Other: Advisory Board. Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Prediction of recessive inheritance for missense variants in human disease

The prediction of pathogenic human missense variants has improved in recent years, but a more granular level of variant characterization is required. Further axes of information need to be incorporated in order to advance the genotype-to-phenotype map. Recent efforts have developed mode of inheritance prediction tools; however, these lack robust validation and their discrimination performance does not support clinical utility, with evidence of them being fundamentally insensitive to recessive acting diseases. Here, we present MOI-Pred, a three-way variant-level mode of inheritance prediction tool aimed at recessive identification for missense variants. MOI-Pred shows strong ability to discriminate missense variants causing autosomal recessive disease (area under the receiver operating characteristic (AUROC)=0.99 and sensitivity=0.85) in an external validation set. Additionally, we introduce an electronic health record (EHR)-based validation approach using real-world clinical data and show that our recessive predictions are enriched for recessive associations with human diseases, demonstrating utility of our method. Mode of inheritance predictions; pathogenic for autosomal recessive (AR) disease, pathogenic for autosomal dominant (AD) disease, or benign, for all possible missense variants in the human genome are available at https://github.com/rondolab/MOI-Pred/.

Mode of inheritance of syndactyly in selected human families in Bahawalnagar, Pakistan

Syndactyly is joining or merging of web in feet and hands digits. It is inherited by autosomal dominant, autosomal recessive, x-linked, and y-linked manner. Its prevalence is around 1 in 2000 live birth. Non-syndromic syndactyly is classified into nine types. In this study, we find out prevalence, percentage, types, and mode of inheritance of syndactyly in families of district Bahawalnagar. The survey was carried out in hospitals, schools, and villages of district Bahawalnagar to find out the patients with congenital syndactyly. Three families with cousin marriages were selected for pedigrees. These families had 2:1 of foot and hand syndactyly. The percentage of complete and incomplete syndactyly was recorded 50% in all families. The mode of inheritance was autosomal dominant and autosomal recessive pattern because of two types of syndactyly type I (SD1) and syndactyly type I-c. In families Bwn1, Bwn2, and Bwn3 the percentage of family members associated with syndactyly was 16%, 9.7%, and 6.89% respectively. It was further noted that all male members of all families were affected with syndactyly. This study finds out the type I (SD1) and type I-c syndactyly in the studied sample population.

Detection of a new deleterious SGCE gene variant in Moroccan family with inherited Myoclonic-dystonia

Myoclonus-Dystonia is a neuropsychiatric disorder with autosomal dominant mode of inheritance with variable severity and incomplete penetrance. Pathogenic variants in SGCE are the most frequent genetic cause of M-D with maternal imprinting. Herein we report a new deleterious variant based on protein modeling analysis (c.662G> T) inherited in moroccan family.

Clinical experience of observation and tactics of management of a patient with ectodermal angydrotic dysplasia

The concept of ectodermal dysplasias covers a group of rare hereditary developmental anomalies that have a variety of phenotypic variants, but are characterized by common signs of underdevelopment or abnormal formation of organs and tissues derived from the ectodermal layer (skin and its derivatives - nails, hair, teeth, nervous system and sensory organs) ... Approximately 25% of ectodermal dysplasias known to date are inherited in an autosomal dominant or autosomal recessive manner; in other cases, the mode of inheritance is unclear. The syndrome is characterized by a wide range of clinical manifestations and may include additional symptoms of damage to other ectodermal, mesodermal, and endodermal structures. Ectodermal anomalies are a manifestation of disturbances in spatial-temporal coordination during the development of the epidermis. They involve genes such as EGF (epidermal growth factor), ED1 (ectodisplasin), EDAR (anhydrotic receptor ectodysplasin 1) and others that regulate the activity of genes involved in epidermal morphogenesis by activating or suppressing transcription factors (in particular, pb3; Koster). So far, only about 20% of genes have been identified that are responsible for about 200 ectodermal dysplasias of various symptoms and severity. This article describes the clinical observation of a patient with a rare disease - ectodermal anhydrotic dysplasia. The literature data on the clinical features of the course of this dermatosis, as well as the features of the course in this patient are presented.

Biotechnological Methods for Buckwheat Breeding

The Fagopyrum genus includes two cultivated species, namely common buckwheat (F. esculentum Moench) and Tartary buckwheat (F. tataricum Gaertn.), and more than 25 wild buckwheat species. The goal of breeders is to improve the properties of cultivated buckwheat with methods of classical breeding, with the support of biotechnological methods or a combination of both. In this paper, we reviewed the possibility to use transcriptomics, genomics, interspecific hybridization, tissue cultures and plant regeneration, molecular markers, genetic transformation, and genome editing to aid in both the breeding of buckwheat and in the identification and production of metabolites important for preserving human health. The key problems in buckwheat breeding are the unknown mode of inheritance of most traits, associated with crop yield and the synthesis of medicinal compounds, low seed yield, shedding of seeds, differential flowering and seed set on branches, and unknown action of genes responsible for the synthesis of buckwheat metabolites of pharmaceutical and medicinal interest.