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Cystic fibrosis is a highly prevalent genetic disorder caused by biallelic pathogenic variants in the CFTR gene, causing an altered function of the exocrine glands and a subsequent spectrum of hypofunctional and degenerative manifestations. The increasing availability of carrier screening programmes, the enhanced life expectancy of patients due to improved treatment and care strategies and the development of more precise and affordable molecular diagnostic tools have prompted a rise in demand of prenatal diagnosis procedures for at-risk couples, including Preimplantation Genetic Testing (PGT). However, challenges remain: heterogeneity among screening programmes, nuances of variant interpretation and availability of novel treatments demand a considerate and knowledgeable approach to genetic counselling. In this work, we retrospectively evaluated the molecular data of 92 unselected couples who received a diagnosis of CFTR-related status and were referred to the genetics clinic at the University Hospital of Padua for genetic counselling on eligibility for PGT. A total of 50 couples were considered eligible for the procedure based on risk of transmitting biallelic pathogenic variants. We report and discuss our experience with this case series in the context of the Italian medical care system and present an overview of the most relevant issues regarding genetic counselling for PGT in CFTR-related disorders. [ABSTRACT FROM AUTHOR]

Primary ovarian failure (POF) is caused by follicle exhaustion and is associated with menstrual irregularities and elevated gonadotropin levels, which lead to infertility before the age of 40 years. The etiology of POI is mostly unknown, but a heterogeneous genetic and familial background can be identified in a subset of cases. Abnormalities in the fragile X mental retardation 1 gene (FMR1) are among the most prevalent monogenic causes of POI. These abnormalities are caused by the expansion of an unstable CGG repeat in the 5′ untranslated region of FMR1. Expansions over 200 repeats cause fragile X syndrome (FXS), whereas expansions between 55 and 200 CGG repeats, which are defined as a fragile X premutation, have been associated with premature ovarian failure type 1 (POF1) in heterozygous females. Preimplantation genetic testing for monogenic diseases (PGT-M) can be proposed when the female carries a premutation or a full mutation. In this narrative review, we aim to recapitulate the clinical and molecular features of POF1 and their implications in the context of PGT-M. [ABSTRACT FROM AUTHOR]

This article reports on a case study of a newborn patient with trichothiodystrophy-3 (TTD3) caused by a novel homozygous variant in the GTF2H5 gene. The patient exhibited a severe phenotype, including congenital ichthyosis, complex cranial anomalies, life-threatening infections, and a complex cardiac malformation, which is unprecedented in TTD3 patients. Trichothiodystrophies are rare genetic disorders characterized by ichthyosis, skin photosensitivity, brittle hair, susceptibility to infections, intellectual impairment, short stature, and decreased fertility. The GTF2H5 gene is crucial for nucleotide excision repair activity and defects in this gene have been associated with TTD3. This case expands our understanding of the clinical and mutational landscape of GTF2H5 and highlights its potential for causing severe multisystemic damage. [Extracted from the article]

This letter discusses the findings of a study that screened an Italian cohort for mutations in the potassium channel subunit Kir4.1 in relation to paroxysmal kinesigenic dyskinesia (PKD). The study identified a specific mutation, c.511C>T, p.Arg171Trp, in a patient with PKD, which had also been previously reported in a Chinese patient with PKD. The mutation was found to result in a reduction of potassium currents, indicating dysfunctional Kir4.1 channels. The study suggests that mutant Kir4.1 may play a role in the development of PKD and highlights the need for further research on the topic. [Extracted from the article]

Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice-site variants in the PNKP gene (NM_007254.4): c.1448+1G > A and c.199-8_199-5del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199-8_199-5del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the PNKP locus., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Primary ovarian failure (POF) is caused by follicle exhaustion and is associated with menstrual irregularities and elevated gonadotropin levels, which lead to infertility before the age of 40 years. The etiology of POI is mostly unknown, but a heterogeneous genetic and familial background can be identified in a subset of cases. Abnormalities in the fragile X mental retardation 1 gene ( FMR1 ) are among the most prevalent monogenic causes of POI. These abnormalities are caused by the expansion of an unstable CGG repeat in the 5' untranslated region of FMR1 . Expansions over 200 repeats cause fragile X syndrome (FXS), whereas expansions between 55 and 200 CGG repeats, which are defined as a fragile X premutation, have been associated with premature ovarian failure type 1 (POF1) in heterozygous females. Preimplantation genetic testing for monogenic diseases (PGT-M) can be proposed when the female carries a premutation or a full mutation. In this narrative review, we aim to recapitulate the clinical and molecular features of POF1 and their implications in the context of PGT-M.