Speech, language, and cognitive impairment are defining features of Kleefstra syndrome but have not been systematically characterised, limiting robust clinical decision making and future planning. We characterised speech, language, and cognition in 103 individuals with Kleefstra syndrome. Language and cognitive ability ranged from average to severely impaired and most verbal individuals had speech production disorders […]
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The Mosaic RASopathy concept : different skin lesions, same systemic manifestations?
Epidermal nevi, are mosaic disorders, caused by mutations during embryogenesis, hence affecting only those cells and tissues which had as a precursor this mutated cell. There are many types of epidermal nevi. Variable anomalies in other organs may be associated. In this paper we reviewed syndromic epidermal nevi, caused by mutations in HRAS, KRAS, NRAS […]
Genotype and phenotype correlation of PHACTR1-related neurological disorders
PHACTR1(phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to infantile epileptic spasms syndrome (IESS). Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin binding sequences overlap with PPP1CA […]
GRN mutation spectrum and genotype–phenotype correlation in Chinese dementia patients: data from PUMCH dementia cohort
Heterozygous mutations in the GRN, especially of the loss of function type, are causative of Frontotemporal dementia (FTD). However, several GRN variants can be found in other neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease. We reported 14 Chinese subjects with the rare variants of GRN (NM_002087.3). They presented with behavioral variant of […]
Clinical implications of VUS reclassification in a single-center series from application of ACMG/AMP classification rules specified for BRCA1/2
The detection of variants of uncertain significance (VUSs) in BRCA1/2 genes poses challenges in counseling and managing cancer patients. In this work, we have reviewed all BRCA1/2 VUSs detected in our clinical service in Bologna (Italy) over the past 11 years following recently developed classification guidelines, yielding a classification rate of 81.3%. This result demonstrates […]
Breast cancer risk in NF1-deleted patients
Neurofibromatosis type 1 (NF1) is a genetic condition characterized by increased risk of developing tumors, as well as various other physical and neurological manifestations. NF1 women were previously reported to have an increased risk of breast cancer. There are different genetic variants causing NF1: in ~5-10% of patients, large deletions of the entire NF1 locus […]
Recontact to return new or updated PALB2 genetic results in the clinical laboratory setting
Duty to re-contact patients for updated genetic test results is a widely discussed topic and is routinely practiced by clinical laboratories. However, publications documenting results from retrospective testing are lacking. Within a cohort of 2977 individuals with Hereditary Breast and Ovarian Cancer and previously negative or inconclusive BRCA1/BRCA2 results, reanalysis found a new pathogenic variant […]
Germline testing of BRCA1, BRCA2, PALB2 and CHEK2 c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of ATM, RAD51C and RAD51D in over 400
Alterations of certain genes may place women at increased risk of developing a subtype of breast cancer not expressing hormone receptors, triple negative breast cancer (TNBC). We undertook a review of the gene alterations seen in women in Manchester with TNBC and showed there is an increased risk of developing TNBC where there is an […]
Reduced penetrance of gene variants causing amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative diseases with shared pathology and genetics . We know how common ALS and FTD are, how often they run in families and how often specific genes are implicated. We used published literature and population-level data about genomic variation to calculate how common disease-causing variants […]
Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia
Classical aniridia is an eye malformation caused by the loss of one working copy of the PAX6 gene, but a minority of cases remain genetically unsolved. We sequenced the whole genomes of 37 affected families (51 individuals) where PAX6 had previously been sequenced but no causative mutation was found. We found a genetic cause in 22 (60%) families. 19 cases had […]