Characterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations.

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.

The impact of a second embryo biopsy for preimplantation genetic testing for monogenic diseases (PGT-M) with inconclusive results on pregnancy potential: results from a matched case-control study.

Purpose: To evaluate whether a second biopsy, following a first diagnostic failure on blastocysts tested for preimplantation genetic testing for monogenic diseases (PGT-M), allows to obtain genetic diagnosis and to what extent this procedure can influence clinical pregnancy and live birth rates compared to the PGT-M process with a successful genetic diagnosis from the first biopsy.

Methods: Embryos from women who underwent PGT-M in an infertility centre and who had been transferred after two biopsies for genetic analysis (n = 27) were matched in a 1:1 ratio accordingly to women's age (± 1 year) and fertility status (fertile vs infertile), as well as with the study period, with embryos who were transferred after receiving a conclusive PGT result straight after the first biopsy (n = 27). The main evaluated outcome was clinical pregnancy rate following embryo transfers in which healthy embryos were transferred after only one biopsy and those in which an embryo was transferred after being re-biopsied.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

Objective: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals.

Homozygous Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature.

The gene encodes for the cardiac isoform of troponin I, a pivotal component of the sarcomeric structure of the myocardium. While heterozygous missense mutations have long been associated with autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of null mutations has been more debated due to the paucity and weak characterization of reported cases and the low penetrance of heterozygous genotypes. In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic null mutations cause a severe form of neonatal dilated cardiomyopathy.

Cantú syndrome: A new case and evolution of clinical conditions during first 2-year follow-up.

Cantú syndrome, or hypertrichotic osteochondrodysplasia, is a rare autosomal dominant disease characterized by congenital hypertrichosis, characteristic dysmorphisms, skeletal abnormalities and cardiomegaly. We report on a 7-year-old girl with congenital generalized hypertrichosis, coarse facial appearance and cardiac involvement, with a de novo heterozygous mutation (c.3461G > A) in the ABCC9 gene.

Extended Glasgow Outcome Scale to Evaluate the Functional Impairment of Patients With Subcortical Band Heterotopia: A Multicentric Cross-sectional Study.

Background: Subcortical band heterotopia (SBH) is a rare malformation of the cortical development characterized by a heterotopic band of gray matter between cortex and ventricles. The clinical presentation typically includes intellectual disability and epilepsy.

Purpose: To evaluate if the Extended Glasgow Outcome Scale-pediatric version (EGOS-ped) is a feasible tool for evaluating the functional disability of patients with (SBH).

Early pediatric palliative care involvement in a child with a large deletion of the short arm (p) of chromosome 10: a case report.

Background: We present a case of a Chinese child with one of the largest terminal deletions (21 Mb) of the short arm of chromosome 10 (10p) reported to date. Distal monosomy 10p is a rare chromosomal disorder characterized by intellectual disability, postnatal growth retardation, structural birth defects and dysmorphisms. Mutations in certain 10p regions have been associated with distinct clinical features, but the real weight of each component cannot be estimated in a large deletion like that of our child; therefore, long-term prognosis is difficult to predict precisely, although it certainly foresees a severe impact on the psychomotor development of the child.

Epigenetics of pregnancy: looking beyond the DNA code.

Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development.

Correction: Martini, A.; Cassina, M. Victor A. McKusick, the "Father of Medical Genetics". 2021, , 636-638.

In the original article [...

Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients.

An increased lifetime risk of epilepsy has been reported in neurofibromatosis type 1 (NF1) patients, ranging between 4% and 14%. To further analyze the correlation between NF1 and epilepsy, we retrospectively reviewed the epidemiologic, clinical, radiological, and molecular data of 784 unselected patients diagnosed with NF1 and referred to the neurofibromatosis outpatient clinics at the University Hospital of Padua. A crude prevalence of epilepsy of 4.

Victor A. McKusick, the "Father of Medical Genetics".

The Special Issue "Genetics of hearing loss" is dedicated to Victor A [...

Genetics & Epigenetics of Hereditary Deafness: An Historical Overview.

Hearing loss (HL) is one of the most common sensory impairments worldwide and represents a critical medical and public health issue. Since the mid-1900s, great efforts have been aimed at understanding the etiology of both syndromic and non-syndromic HL and identifying correlations with specific audiological phenotypes. The extraordinary discoveries in the field of molecular genetics during the last three decades have contributed substantially to the current knowledge.

DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature.

Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. gene encodes gamma actin, the predominant actin protein in the cytoskeleton of auditory hair cells; its normal expression and function are essential for the stereocilia maintenance. Different gain-of-function pathogenic variants of have been associated with two major phenotypes: DFNA20/26 and Baraitser-Winter syndrome, a multiple congenital anomaly disorder.

Genotype-phenotype correlation in Gordon's syndrome: report of two cases carrying novel heterozygous mutations.

Gordon's syndrome, known also as Pseudohypoaldosteronism type II is a rare inherited dominant form of low-renin hypertension associated with hyperkalemia and metabolic acidosis. Four genes related to the regulation of the NaCl co-symporter NCC have been discovered associated to Gordon phenotypes: WINK 1 and WINK4, which, along with WNK2 and WNK3, encode a family of WNK-kinases, and KLHL3 and CUL3 encoding respectively, Kelch-like 3 protein and cullin. Heterozygous mutations in these genes constitutively activate NCC leading to abnormally increased salt reabsorption and salt-sensitive hypertension.

Craniosynostosis is a feature of CHD7-related CHARGE syndrome.

CHARGE syndrome is a rare genetic multiple-malformation disorder characterized by wide phenotypic variability. It is often caused by heterozygous variants in CHD7 and, more rarely, SEMA3E. Although craniofacial alterations are frequent in this condition, to date craniosynostosis is not considered part of the clinical spectrum.

Hybrid Minigene Assay: An Efficient Tool to Characterize mRNA Splicing Profiles of Variants.

Neurofibromatosis type 1 (NF1) is caused by heterozygous loss of function mutations in the gene. Although patients are diagnosed according to clinical criteria and few genotype-phenotype correlations are known, molecular analysis remains important. displays allelic heterogeneity, with a high proportion of variants affecting splicing, including deep intronic alleles and changes outside the canonical splice sites, making validation problematic.

Auditory Outcome after Cochlear Implantation in Children with DFNB7/11 Caused by Pathogenic Variants in TMC1 Gene.

Introduction: Non-syndromic hereditary hearing loss is characterized by extreme genetic heterogeneity. So far, more than 100 pathogenic or likely pathogenic variants in TMC1 gene have been reported in patients with autosomal recessive hearing loss (HL) DFNB7/11. The prevailing auditory phenotype of individuals with DFNB7/11 is congenital, profound, bilateral HL, but the functional outcome after cochlear implantation (CI) described in the literature is variable.

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester.

Biallelic mutations in the gene cause a novel primary ciliopathy.

Background: Dysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis.

Objective: To investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies.