2024

Cerebral inflammation in a patient with Kabuki syndrome

Wed, 18 Dec 2024 23:00:00 GMT

The in-depth characterization of patients with common variable immunodeficiency (CVID) is a recent advancement, revealing a complex genetic landscape.

The primary cilium gene CPLANE1 is required for peripheral nervous system development

Sun, 15 Dec 2024 23:00:00 GMT

Ciliopathies are a group of neurodevelopmental disorders characterized by the dysfunction of the primary cilium.

Further delineation of the SCAF4-associated neurodevelopmental disorder

Wed, 11 Dec 2024 23:00:00 GMT

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited.

Holiday Season 2024 - Special Opening Hours

Björn Kleijkers, Infrastructure & Communications Manager — Wed, 04 Dec 2024 23:00:00 GMT

The Institute of Medical Genetics at the University of Zurich will be open during the holiday season on specific days and times. Here you will find all the information.

Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability

Wed, 04 Dec 2024 23:00:00 GMT

This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in GTF3C3, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.

Paediatric Personalized Research Network Switzerland (SwissPedHealth): a joint paediatric national data stream

Sat, 30 Nov 2024 23:00:00 GMT

Children represent a large and vulnerable patient group. However, the evidence base for most paediatric diagnostic and therapeutic procedures remains limited or is often inferred from adults.

Nachruf John M. Opitz

Anita Rauch, André Reis — Thu, 28 Nov 2024 23:00:00 GMT

geboren in Hamburg am 15.08.1935, verstorben 31. Oktober 2023 in Salt Lake City, Utah, U.S.A

Letter to the Editor

Mon, 18 Nov 2024 23:00:00 GMT

Pediatric Acute B-Lymphoblastic Leukemia Presenting as Hypereosinophilia With Lung Involvement and Elevated Immunoglobulin E Levels.

Loss of tissue-type plasminogen activator causes multiple developmental anomalies.

Fri, 15 Nov 2024 23:00:00 GMT

Hydrocephalus and Dandy-Walker malformation are among the most common congenital brain anomalies.

The new University Children's Hospital Zurich

Wed, 16 Oct 2024 13:28:34 GMT

From 2^ndof November, the Children's Hospital Zurich will be located at a new address.

In the future, your child's medical and nursing care will be provided in a modern new building.

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

Sun, 13 Oct 2024 22:00:00 GMT

Joubert Syndrome gene dysfunction in zebrafish leads to abnormal brain cilia, altered transcription of neuron-associated genes and abnormal swimming behaviour despite normal brain morphology.

Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder

Thu, 19 Sep 2024 22:00:00 GMT

De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism.

Nanopore Deep Sequencing as a Tool to Characterize and Quantify Aberrant Splicing Caused by Variants in Inherited Retinal Dystrophy Genes

Mon, 02 Sep 2024 22:00:00 GMT

The contribution of splicing variants to molecular diagnostics of inherited diseases is reported to be less than 10%.

Faulty Gene Makes Brain Too Big – or Too Small

Paranchai Boonsawat and Anita Rauch, Institute of Medical Genetics, UZH — Wed, 21 Aug 2024 22:00:00 GMT

A gene called ZNRF3, known to be involved in cancer, also messes with the mind. The human brain relies on two copies of this gene to build a right-sized brain. If one of the copies is defective, the brain will be either too small or too large – known as mirror effect –, leading to various neurological symptoms.

Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia

Mon, 12 Aug 2024 22:00:00 GMT

Background
Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only eight documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1.

Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling

Thu, 15 Aug 2024 22:00:00 GMT

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development.

Further evidence for an attenuated phenotype of in‐frame DMD deletions affecting the central rod domain of dystrophin around exon 48

Olga Bürger, Angelika Humbel, Ivan Ivanovski, Alessandra Baumer, Anita Rauch — Sun, 18 Aug 2024 22:00:00 GMT

Alterations in the X-linked recessive DMD gene cause dystrophinopathies with a broad clinical spectrum most commonly ranging from Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to cardiomyopathy or intellectual disability.

SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline

Wed, 04 Sep 2024 22:00:00 GMT

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These “selfish” mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father’s age, and high apparent germline mutation rate.

Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy

Wed, 10 Jul 2024 22:00:00 GMT

To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy.

SwissGenVar: A Platform for Clinical-Grade Interpretation

Sun, 16 Jun 2024 22:00:00 GMT

To support clinical decision making, all five Swiss academic institutions for Medical Genetics joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data .

Limited Added Diagnostic Value of Whole Genome Sequencing in Genetic Testing of Inherited Retinal Diseases in a Swiss Patient Cohort

Wed, 12 Jun 2024 22:00:00 GMT

The purpose of this study was to assess the added diagnostic value of whole genome sequencing (WGS) for patients with inherited retinal diseases (IRDs) who remained undiagnosed after whole exome sequencing (WES).

Prof Dr med Ruxandra Bachmann-Gagescu appointed Associate Professor of Developmental Genetics

Tue, 04 Jun 2024 22:00:00 GMT

Ruxandra Bachmann-Gagescu was appointed Associate Double Professor of Developmental Genetics at the Institute of Molecular Biology of the Faculty of Mathematics and Natural Sciences and the Institute of Medical Genetics of the Faculty of Medicine at the University of Zurich in October 2023.

Variant-specific pathophysiological mechanisms of AFF3

Wed, 29 May 2024 22:00:00 GMT

Background

We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Wed, 15 May 2024 22:00:00 GMT

Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51).

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Mon, 13 May 2024 22:00:00 GMT

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene.

Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

Sun, 12 May 2024 22:00:00 GMT

Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy.

DPF2-related Coffin-Siris syndrome type 7 in two generations

Sun, 05 May 2024 22:00:00 GMT

To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which localized in the PHD1/PHD2 domains of DPF2.

Read the full article here.

Systematic identification of structure-specific protein–protein interactions

Thu, 02 May 2024 22:00:00 GMT

The physical interactome of a protein can be altered upon perturbation, modulating cell physiology and contributing to disease. Identifying interactome differences of normal and disease states of proteins could help understand disease mechanisms, but current methods do not pinpoint structure-specific PPIs and interaction interfaces proteome-wide.

Network Migration

Björn Kleijkers, Infrastructure & Communications Manager — Thu, 18 Apr 2024 22:00:00 GMT

We would like to inform you that the institute will carry out a migration of the internal and external network from 1 May till noon 2 May.

Olfactory Receptor OR2K2 Expression in Human Choroid Plexus as a Potential Marker in Early Sporadic Alzheimer’s Disease

Wed, 20 Mar 2024 23:00:00 GMT

Epithelial cells comprising the choroid plexus (CP) form a crucial barrier between the blood
and the cerebrospinal fluid, thereby assuming a central position in brain homeostasis and signaling.
Mounting evidence suggests that the impairment of CP function may be a significant contributor to
Alzheimer’s disease (AD) pathogenesis.

Read the full article here.

Easter Closing

Björn Kleijkers — Tue, 19 Mar 2024 23:00:00 GMT

The institute is closed from Thursday, 28 March, 16:00, until Easter Monday, 1 April.

Please note that we will accept samples until 17:00.
We will be back as usual on Tuesday 2nd April!

E-mail Outage of 8th of March 2024

Björn Kleijkers — Sat, 09 Mar 2024 23:00:00 GMT

The Institute of Medical Genetics experienced an email outage. This has now been resolved. More information can be found in this article.

SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation

Mon, 26 Feb 2024 23:00:00 GMT

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects.

Read the full article here.

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Wed, 21 Feb 2024 23:00:00 GMT

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. We dissected the mechanisms of scoliosis onset in a zebrafish mutant for the rpgrip1l gene encoding a ciliary transition zone protein. rpgrip1l mutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles.

Read the full article here.

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

Wed, 14 Feb 2024 23:00:00 GMT

Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions.

Read this preprint in full in our Preprint section.

Utilizing Genetic Linkage and Rare Variant Association Studies to Unravel Novel Disease Etiologies

Elena M. Cabello Ferrete — Mon, 19 Feb 2024 23:00:00 GMT

This thesis aims to use bioinformatic approaches to elucidate the underlying genetic causes of three different diseases.

Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry

Wed, 14 Feb 2024 23:00:00 GMT

Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005–2014 and prospectively from 2015 onwards.

Identification of the DNA methylation signature of Mowat-Wilson syndrome

Mon, 12 Feb 2024 23:00:00 GMT

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment.

Read this article in full at the European Journal of Human Genetics.

Molecular and Phenotypic Characterization of the RORB-Related Disorder

Mon, 22 Jan 2024 23:00:00 GMT

Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. Read this article in full at Neurology

Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies

Mon, 15 Jan 2024 23:00:00 GMT

Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. Read the full pre-print article online at medRxiv

Unveiling DNA methylation in Alzheimer’s disease: a review of array-based human brain studies.

Alves, Victoria Cunha; Carro, Eva; Figueiro-Silva, Joana — Sun, 07 Jan 2024 23:00:00 GMT

The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms, particularly DNA methylation. This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.

Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor

Mon, 01 Jan 2024 23:00:00 GMT

Somatic variants in the NOTCH pathway regulator FBXW7 are frequently seen in a variety of malignancies. Read this publication online in the American Journal of Medical Genetics