Bert Callewaert

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Verified

Bert verified their affiliation via an institutional email.

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• MD, PhD
• Professor (Full) at Ghent University

Zebrafish serve as a valuable model organism for studying human genetic diseases. While generating knockout lines is relatively straightforward, introducing precise disease-specific genetic variants by knock-in (KI) remains challenging. KI lines, however, enable more accurate studies of molecular and physiological consequences of genetic diseases....

RNA sequencing (RNA-seq) has become key to complementing exome and genome sequencing for variant interpretation. We present a minimally invasive RNA-seq protocol using short-term cultured peripheral blood mononuclear cells (PBMCs) with and without cycloheximide treatment, enabling detection of transcripts subject to nonsense-mediated decay. While b...

Background Decisions to split two or more phenotypic manifestations related to genetic variations within the same gene can be challenging, especially during the early stages of syndrome discovery. Genotype-based diagnostics with artificial intelligence (AI)-driven approaches using next-generation phenotyping (NGP) and DNA methylation (DNAm) can be...

ALPK3 encodes the protein alpha-kinase 3, an essential cardiac-enriched atypical a-kinase that inserts in the nuclear envelope and the sarcomere M-band of cardiac myocytes, functioning to aid in myosin-mediated force buffering and sarcomere proteostasis. Previously, bi-allelic loss-of-function ALPK3 variants have been reported causative in a severe...

The FOXG1 transcription factor is a crucial regulator of embryonic brain development. Pathogenic FOXG1 variants cause FOXG1 syndrome. Although structural variants (SVs) in the non-coding region downstream of FOXG1 have been reported in 38 individuals with FOXG1 syndrome-like characteristics, the regulatory pathomechanisms remain unknown. We identif...

Purpose Congenital cutis laxa (CL) syndromes encompass a diverse group of inherited connective tissue disorders characterized by redundant, wrinkled, and inelastic skin, often with systemic involvement. Ocular involvement in CL has sporadically been reported albeit without systematic, comprehensive ocular assessment. The purpose of this study was t...

Variations in foot arch morphology, including flat feet (pes planus) and high arches (pes cavus), range from asymptomatic to debilitating. Limited research exists on the genetics of foot arch geometry. This systematic review aims to identify single nucleotide polymorphisms (SNPs) linked to foot arch morphology. The review protocol was registered in...

Genomic variants of uncertain significance (VUS) impede clinical decision-making. In this study, we use a knock-in strategy in zebrafish to evaluate the COL1A2 c.2123G>A VUS, identified in a 59-year-old female with recurrent fractures. Using prime editing, we obtained different zebrafish lines respectively harboring the VUS, a known pathogenic vari...

Zebrafish serve as a valuable model organism for studying human genetic diseases. While generating knockout lines is relatively straightforward, introducing precise disease-specific genetic variants by knock-in (KI) remains challenging. KI lines, however, enable more accurate studies of molecular and physiological consequences of genetic diseases....

The etiology of congenital heart disease (CHD) is complex, comprising both genetic and environmental factors. Despite documented familial occurrences, the genetic etiology remains largely elusive. Trio exome sequencing identified a heterozygous FLT4 splice site variant in two families with respectively tetralogy of Fallot (TOF), and variable CHD co...

Focal facial dermal dysplasia (FFDD) type IV is a rare inherited facial defect caused by biallelic variants in CYP26C1. This study reports two novel Belgian FFDD type IV cases, both homozygous for a recurrent CYP26C1 frameshift variant, with a common 700 kb haplotype, indicating a founder effect. image

Background In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clini...

Supramolecular extracellular matrix (ECM) networks play an essential role in skin architecture and function. Elastin microfibril interface-located proteins (EMILINs) comprise a family of three extracellular glycoproteins that serve as essential structural components of the elastin/fibrillin microfibril network, and exert crucial functions in cellul...

Structural variants (SVs) are important contributors to human disease. Their characterization remains however difficult due to their size and association with repetitive regions. Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full. In this study, we selected six indi...

8q21.11 microdeletions encompassing the gene encoding transcription factor ZFHX4, have previously been associated by us with a syndromic form of intellectual disability, hypotonia, decreased balance and hearing loss. Here, we report on 57 individuals, 52 probands and 5 affected family members, with protein truncating variants (n=36), (micro)deletio...

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in...

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders G...

Structural variants (SVs) are important contributors to human disease. Their characterization remains however difficult due to their size and association with repetitive regions. Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full. In this study, we selected six indi...

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, j...

Familial chylomicronemia syndrome (FCS) (OMIM: 238600) is a rare autosomal recessive disease caused by a biallelic loss-of-function mutation in the lipoprotein lipase (LPL) complex which includes LPL and its co-factors. Patients with FCS have severe hypertiglyceridemia (> 2000 mg/dL). We describe a 15-month-old boy with repeated pancreatitis episod...

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tum...

Thoracic aortic aneurysm and dissection (TAAD) associates with a high mortality rate. Despite the existence of different mouse models for TAAD, the underlying disease mechanisms remain elusive. Treatment options are limited and mainly consist of surgical repair at critical aortic diameters as current pharmacological interventions are unable to stop...

Aicardi–Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early‐onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1 , RNASEH2B , RNASEH2C , RNASEH2A , SAMHD1 , ADAR , IFIH1 , LSM11 , and RNU7 ‐ 1 . Diagnosis...

Background As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods We analyse evidence for inher...

Background Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. Metho...

Cutis laxa syndromes are a heterogeneous group of multisystem disorders with prominent connective tissue features including loose redundant skin folds, a clinical hallmark shared among all subtypes. The skin laxity results from severe dermal elastic fibre fragmentation. The molecular defects underlying congenital forms of cutis laxa may affect any...

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function variation in ZFHX3 as a novel cause for syndromic intellectual disability (ID). ZFHX3, previously known as ATBF1, is a zinc-finger homeodomain transcription factor involved in multiple biological processes including...

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-cau...

Background As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. Methods We analyse evidence for inheri...

Epidermal nevus syndrome (ENS) comprises a heterogeneous group of neurocutaneous syndromes associated with the presence of epidermal nevi and variable extracutaneous manifestations. Postzygotic activating HRAS pathogenic variants were previously identified in nevus sebaceous (NS), keratinocytic epidermal nevus (KEN), and different ENS, including Sc...

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotoni...

Purpose: To provide differentiating clinical criteria, evaluate genotype-phenotype correlations, and propose management guidelines for the different ATP7A-related copper transport disorders. Methods: We performed a systematic literature review by querying the MEDLINE and Embase databases identifying 143 relevant papers, and included data on the...

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants...

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay...

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifact...

Background: Ligneous conjunctivitis is a very rare form of pseudomembranous conjunctivitis with few published cases in literature. We aim to describe the ocular findings and treatment in an infant with ligneous conjunctivitis resembling preseptal cellulitis on presentation. Materials and methods: Case report of a 3-month-old girl who was referre...

We present a long-term follow-up in a 17-year-old girl with DGAT1-related diarrhea, an autosomal recessive disorder characterized by impaired triglyceride absorption. Neonatal presentation included severe congenital diarrhea, protein-losing enteropathy, and failure to thrive requiring total parenteral nutrition. Duodenal biopsies revealed apoptotic...

Biallelic variants of the gene encoding for the zinc‐finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among...

Background In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics. Methods Patients referred...

Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) that include a broad phenotypic spectrum ranging from late-onset limb-girdle muscular dystrophy to severe muscle–eye–brain disease, Walker–Warburg syndrome, and Fukuyama congenital muscular dystrophy. In addition to clinical heterogeneity, CMDs are characterized by genetic h...

Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASo...

Purpose This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methy...

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is geneti...

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the lite...

Asprosin, the C-terminal furin cleavage product of profibrillin-1, was reported to act as a hormone that circulates at nanomolar levels and is recruited to the liver where it induces G protein-coupled activation of the cAMP-PKA pathway and stimulates rapid glucose release into the circulation. Although derived from profibrillin-1, a multidomain ext...

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics...

Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the sk...

Purpose This study aimed to describe a multisystemic disorder featuring cardiovascular, facial, musculoskeletal, and cutaneous anomalies caused by heterozygous loss-of-function variants in TAB2. Methods Affected individuals were analyzed by next-generation technologies and genomic array. The presumed loss-of-function effect of identified variants...

Objective Facial dysostosis is a group of rare craniofacial congenital disabilities requiring multidisciplinary long-term care. This report presents the phenotypic and genotypic information from South India. Design The study is a case series. Setting This was an international collaborative study involving a tertiary craniofacial clinic and medica...

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic conte...

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine...

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhan...

Ciliopathies are a group of clinical and molecular heterogeneous conditions with pleiotropic manifestations affecting the central nervous system, renal, liver, skeletal, and ocular systems. Biallelic pathogenic variants in DCDC2 cause a ciliopathy primarily presenting with neonatal sclerosing cholangitis (NSC). Pathogenic variants in DCDC2 have fur...

The inability to maintain a strictly regulated endo(lyso)somal acidic pH through the proton-pumping action of the vacuolar-ATPases (v-ATPases) has been associated with various human diseases including heritable connective tissue disorders. Autosomal recessive (AR) cutis laxa (CL) type 2C syndrome is associated with genetic defects in the ATP6V1E1 g...

Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFβ in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalit...

We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy‐textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post‐mortem examination in two of the babies furthe...

Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendel...

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Els...

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic cont...

Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-ol...

IQSEC2 mutations are associated with IQSEC2‐related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype–phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2‐related ID a wide phenotypic diversity has been described in Ret...

Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent...

The inability to maintain a strictly regulated endo(lyso)somal acidic pH through the proton-pumping action of the vacuolar-ATPases has been associated with various human diseases including heritable connective tissue disorders, neurodegenerative diseases and cancer. Multiple studies have investigated the pleiotropic effects of reduced acidification...

The CAMTA1‐associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and...

Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Resul...

Cutis laxa (CL) syndromes comprise a rare group of multisystem disorders that share loose redundant skin folds as hallmark clinical feature. CL results from impaired elastic fiber assembly and homeostasis, and the known underlying gene defects affect different extracellular matrix proteins, intracellular trafficking, or cellular metabolism. Due to...

Erratum for: Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa. Van Damme T, Gardeitchik T, Mohamed M, Guerrero-Castillo S, Freisinger P, Guillemyn B, Kariminejad A, Dalloyaux D, van Kraaij S, Lefeber DJ, Syx D, Steyaert W, De Rycke R, Hoischen A, Kamsteeg EJ, Wong SY, van Scherpenzeel M, Jamali P, Brandt U, Nijtmans L, Korenke...

Resumen En los últimos años, la genética ha adquirido merecidamente un lugar importante en casi todas las disciplinas médicas, y este también es el caso en el campo de las cardiopatías congénitas. Esto no solo ha llevado a una mejor comprensión de la fisiopatología de los defectos cardiacos congénitos, sino que también conlleva un impacto positivo...

Genetics has rightly acquired an important place in almost all medical disciplines in recent years and this is certainly the case in the field of congenital cardiology. Not only has this led to greater insight into the pathophysiology of congenital heart defects but it also has a beneficial impact on patient management. Integration of clinical gene...

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patient...

UBE2A deficiency, that is, intellectual disability (ID) Nascimento type (MIM 300860), is an X‐linked syndrome characterized by developmental delay, moderate to severe ID, seizures, dysmorphisms, skin anomalies, and urogenital malformations. Forty affected subjects have been reported thus far, with 31 cases having intragenic UBE2A variants. Here, we...

To date 45 autosomal recessive disease-causing variants are reported in the FKBP10 gene. Those variant were found to be associated with Osteogenesis Imperfecta (OI) for which the hallmark phenotype is bone fractuers or Bruck Syndrome (BS) where bone fractures are accompanied with contractures. In addition, a specific homozygous FKBP10 mutation (p.T...