Hermine A. van Duyvenvoorde

Leiden University

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Jan M. Wit

Leiden University

Monique Losekoot

Leiden University

M.J.E. Walenkamp

Vrije Universiteit Amsterdam

Sarina G. Kant

Leiden University

Wilma Oostdijk

Leiden University

Claudia Ruivenkamp

Leiden University Medical Center

Vivian Hwa

University of Cincinnati

Marcel Karperien

University of Twente

Horacio M. Domené

Hospital General de Niños Ricardo Gutierrez

Alberto M. Pereira

Leiden University Medical Center

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Leiden University Medical Center

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Leiden University

Radboud University Nijmegen

Radboud University Medical Center

Erasmus University Rotterdam

Erasmus MC

University Medical Center

University of Amsterdam

Inserm

Pediatrics and Genetics

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Contents Vol. 80, 2013

Hormone Research in Paediatrics (2013)

M.J.E. Walenkamp Jürgen Klammt Eva Feigerlová Monique Losekoot Hermine A. van Duyvenvoorde

10.1159/000357577

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Genetic findings in short Turkish children born to consanguineous parents

Hormone Research in Paediatrics (2024)

Sjoerd D. Joustra Emregül Işık Jan M. Wit Gönül Çatlı Ahmet Anık

The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented.

Consanguineous Marriage

Microcephaly

10.1159/000539696

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Citations (1)

Elucidation of the Genetic Cause in Dutch Limb Girdle Muscular Dystrophy Families: A 27-Year’s Journey

Journal of Neuromuscular Diseases (2020)

Leroy ten Dam Marianne de Visser Ieke B. Ginjaar Hermine A. van Duyvenvoorde Silvana van Koningsbruggen

A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy (LGMD) patients from 68 families has been subject to genetic testing over the last 20 years. After subsequent targeted gene analysis around two thirds (45/68) of the families had received a genetic diagnosis in 2013.To describe the results of further genetic testing in the remaining undiagnosed limb girdle muscular dystrophy families in this cohort.In the families of the cohort for whom no genetic diagnosis was established (n = 23) further testing using Sanger sequencing, next generation sequencing with gene panel analysis or whole-exome sequencing was performed. In one case DNA analysis for facioscapulohumeral dystrophy type 1 was carried out.In eight families no additional genetic tests could be performed. In 12 of the remaining 15 families in which additional testing could be performed a genetic diagnosis was established: two LGMDR1 calpain3-related families with CAPN3 mutations, one LGMDR2 dysferlin-related family with DYSF mutations, three sarcoglycanopathy families (LGMDR3-5 α-, β- and γ-sarcoglycan-related) with SGCA/SGCB/SGCG mutations, one LGMDR8 TRIM 32-related family with TRIM32 mutations, two LGMDR19 GMPPB-related families with GMPPB mutations, one family with MICU1-related myopathy, one family with FLNC-related myopathy and one family with facioscapulohumeral dystrophy type 1. At this moment a genetic diagnosis has been made in 57 of the 60 families of which DNA was available (95%).A genetic diagnosis is obtained in 95% of the families of the original Dutch LGMD cohort of which DNA was available.

Limb-girdle muscular dystrophy

Sanger sequencing

Dysferlin

10.3233/jnd-200585

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Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit

European Journal of Endocrinology (2008)

Hermine A. van Duyvenvoorde Marlies Kempers Th.B. Twickler J. van Doorn W. J. M. Gerver

Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers.Three short Kurdish brothers and their relatives.The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives.The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

Heterozygote advantage

Compound heterozygosity

Microcephaly

10.1530/eje-08-0081

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The Dutch Dystrophinopathy Database: A National Registry with Standardized Patient and Clinician Reported Real-World Data

Journal of Neuromuscular Diseases (2024)

Nienke M. van de Velde Yvonne D. Krom J. Bongers R.J.A. Hoek N. Ikelaar

Duchenne and Becker muscular dystrophy lack curative treatments. Registers can facilitate therapy development, serving as a platform to study epidemiology, assess clinical trial feasibility, identify eligible candidates, collect real-world data, perform post-market surveillance, and collaborate in (inter)national data-driven initiatives.

10.3233/jnd-240061

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Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes

Frontiers in Endocrinology (2021)

Birgit Weiß Birgit Eberle Ralph Roeth Christiaan de Bruin Julian C. Lui

Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in CEP104, CROCC, NEK1, TOM1L2 , and TSTD2 predicted as damaging were found to be shared between the four tall family members. Three of the five genes ( CEP104, CROCC , and NEK1 ) belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes.

Candidate gene

Sanger sequencing

Mendelian inheritance

10.3389/fendo.2021.660731

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Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives

Nucleic Acid Therapeutics (2021)

Matthis Synofzik Willeke M. C. van Roon‐Mom Georg Marckmann Hermine A. van Duyvenvoorde Holm Graeßner

Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.

Orphan drug

Prioritization

Regulatory Science

10.1089/nat.2021.0039

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Citations (53)

Supplementary Material for: Copy Number Variants in Short Children Born Small for Gestational Age

Figshare (2014)

Jan M. Wit Hermine A. van Duyvenvoorde Jan B. van Klinken J. Caliebe Bosch C.A.J.

Background/Aims: In addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature. Methods: Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information. Results: CNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature. Conclusion: SNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes.

10.6084/m9.figshare.5127034

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The neurocognitive profile of adults with Becker muscular dystrophy in the Netherlands

Journal of Neuromuscular Diseases (2022)

Zaïda Koeks Danique M. J. Hellebrekers Nienke M. van de Velde Iris Alleman Pietro Spitali

In Becker muscular dystrophy evidence for neurocognitive and behavioral comorbidity is evolving. More insight into the extend of these problems is of great importance for early detection and remediation in clinical practice.In this study we aimed to describe the neurocognitive and behavioral features of a Dutch adult cohort of BMD patients, and to evaluate correlations to motor function outcomes.28 adult BMD patients were included. Intelligence, executive functioning, verbal memory and reaction times were assessed cross-sectionally. Additionally, patients completed questionnaires on behavioral and emotional symptoms, psychosocial and executive functions. Results were compared to normative data and correlated with disease severity as measured by the 10-meter run/walk test and Performance of the Upper Limb version 1.2.15 patients (53.6%) had a high educational level despite frequent grade repeating (48.3%) during primary or secondary school. Neuropsychological testing revealed that intellectual abilities, verbal memory, processing speed and executive functioning were statistically significant below average, but still within normal range. Regarding outcomes of the behavioral questionnaires, no significant differences were reported compared to the norm population. No relevant correlations with disease severity were found.This cohort of adult BMD patients exhibits minor cognitive impairments and no significant behavioral problems. The lower outcomes on processing speed and verbal memory, combined with the relatively high prevalence of grade repeating during primary and secondary school, implies that these minor impairments played a role in childhood. However, the on average high educational levels suggests that they grow out of their cognitive impairments with ageing.

Neurocognitive

10.3233/jnd-210770

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Citations (3)

Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome

JCI Insight (2024)

Avinaash Maharaj Emily Cottrell Thatchawan Thanasupawat Sjoerd D. Joustra Barbara L. Triggs‐Raine

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 protein expression and nuclear localization were assessed. Two Hmga2-knockin mouse models were generated. Five clinical SRS patients harbored HMGA2 variants with differing functional impacts: 2 stop-gain nonsense variants (c.49G>T, c.52C>T), c.166A>G missense variant, and 2 frameshift variants (c.144delC, c.145delA) leading to an identical, extended-length protein. Phenotypic features were highly variable. Nuclear localization was reduced/absent for all variants except c.166A>G. Homozygous knockin mice recapitulating the c.166A>G variant (Hmga2K56E) exhibited a growth-restricted phenotype. An Hmga2Ter76-knockin mouse model lacked detectable full-length Hmga2 protein, similarly to patient 3 and 5 variants. These mice were infertile, with a pygmy phenotype. We report a heterogeneous group of individuals with SRS harboring variants in HMGA2 and describe the first Hmga2 missense knockin mouse model (Hmga2K56E) to our knowledge causing a growth-restricted phenotype. In patients with clinical features of SRS but negative genetic screening, HMGA2 should be included in next-generation sequencing testing approaches.

HMGA2

Nonsense

10.1172/jci.insight.169425

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Citations (4)