Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review.

Rationale: Gaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity.

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance.

Background: Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to long QT syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C > T:p.

Mild Isolated Congenital Central Hypothyroidism Due to a Novel Homozygous Variant in : A Case Report.

Pathogenic variants in are known to cause severe isolated central congenital hypothyroidism (CH). In this study, we present the clinical, biochemical, and genetic features of the first patient with a mild central CH phenotype. We identified a novel homozygous variant in : (Chr1: NM_000549.

A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain significance in type 1 long QT syndrome.

Background: Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%.

Case series, chemotherapy-induced cardiomyopathy: mind the family history!

Background: Cardiotoxicity presenting as cardiomyopathy is a common side effect in cancer treatment especially with anthracyclines. The role of genetic predisposition is still being investigated.

Case Summary: Four unrelated patients with a familial burden for cardiac disease, who developed cardiomyopathy after anthracycline treatment are presented.

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.

Defective Levothyroxine Response in a Patient with Dyshormonogenic Congenital Hypothyroidism Caused by a Concurrent Pathogenic Variant in Thyroid Hormone Receptor-β.

Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in , causing resistance to TH (RTH-β).

Early Lethal Noncompaction Cardiomyopathy in Siblings With Compound Heterozygous RYR2 Variant.

Two siblings presented with early lethal noncompaction cardiomyopathy (NCCM). Both carry compound heterozygous variants in the ryanodine receptor gene (RYR2). Evolving animal and human data have begun to implicate a role for RYR2 dysfunction in the development of NCCM.

Pasireotide treatment for severe congenital hyperinsulinism due to a homozygous ABCC8 mutation.

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion.

Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma.

Background And Aims: Adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) deficiency may lead to progressive familial intrahepatic cholestasis type 3 (PFIC3), biliary cirrhosis, low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptive-induced cholestasis (CIC) or may remain asymptomatic. The long-term course, quality of life and histology were investigated in ABCB4 deficiency.

Methods: Adult carriers of ABCB4 gene variants from two regional academic centres were analysed by history taking, electronic patient files, physical examination, blood analysis, abdominal ultrasound (US) and liver elastography.

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

Background: Genetic heterogeneity is common in inherited cardiac diseases. Next-generation sequencing gene panels are therefore suitable for genetic diagnosis. We describe the results of implementation of cardiomyopathy and arrhythmia gene panels in clinical care.

Large next-generation sequencing gene panels in genetic heart disease: challenges in clinical practice.

Background: Next-generation sequencing gene panels are increasingly used for genetic diagnosis in inherited cardiac diseases. Besides pathogenic variants, multiple variants, variants of uncertain significance (VUS) and incidental findings can be detected. Such test results can be challenging for counselling and clinical decision making.

Mutations in IRS4 are associated with central hypothyroidism.

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern.

Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases.

Congenital methaemoglobinaemia in a 61-year-old patient with normal haemoglobin levels.

A 61-year-old Ghanaian woman presented with dizziness and low oxygen saturations whereupon a methaemoglobin level of 24.9% was obtained. Initially it was thought to be caused by an unknown toxin.