Publications by authors named "Raoul C Hennekam"

305 Publications

Large-scale open-source three-dimensional growth curves for clinical facial assessment and objective description of facial dysmorphism.

Sci Rep 2021 06 9;11(1):12175. Epub 2021 Jun 9.

Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium.

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.
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http://dx.doi.org/10.1038/s41598-021-91465-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190313PMC
June 2021

3D analysis of facial morphology in Dutch children with cancer.

Comput Methods Programs Biomed 2021 Jun 9;205:106093. Epub 2021 Apr 9.

Department of Human Genetics, KU Leuven, Leuven, Belgium; Big Data Institute and Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, United Kingdom.

Background and Objective; Genetic risk factors for childhood cancer may also influence facial morphology. 3D photography can be used in the recognition of differences in face shape among individuals. In previous research, 3D facial photography was used to identify increased facial asymmetry and greater deviation from normal facial morphology in a group of individuals with distinct morphological features who had childhood cancer compared to healthy controls. In this study, we aim to determine whether there is a difference in facial morphology between children with cancer without previously selected morphological features and healthy controls, detected with 3D facial photography.

Methods: Facial 3D photographic images were obtained of children with a newly diagnosed malignancy. The resulting sample comprised 13 different cancer types. Patients were excluded if they had a known genetic cause of the cancer. Patients were compared to healthy controls, matched for sex, age and ethnic background. The degree of asymmetry and overall deviation of an individual's face from an age and sex typical control face were measured.

Results: A total of 163 patients of European descent were included. No significant difference in asymmetry between patients and controls could be identified. On average, patients deviated more from an age and sex typical face than the controls.

Conclusion: This study shows that children with cancer deviate more than controls, possibly suggesting a higher prevalence of genetic anomalies within this group. The results suggest that this is not sufficient to discriminate patients from controls. Further research is necessary to explore the patterns of individual variation among the overall deviation of patients and controls.
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http://dx.doi.org/10.1016/j.cmpb.2021.106093DOI Listing
June 2021

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study.

Fam Cancer 2021 Oct 9;20(4):263-271. Epub 2021 Mar 9.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.
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http://dx.doi.org/10.1007/s10689-021-00237-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484098PMC
October 2021

NGLY1 deficiency: Novel variants and literature review.

Eur J Med Genet 2021 Mar 23;64(3):104146. Epub 2021 Jan 23.

Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

NGLY1 deficiency is a recently described autosomal recessive disorder, involved in deglycosylation of proteins, and for that reason grouped as the congenital disorders of deglycosylation together with the lysosomal storage disorders. The typical phenotype is characterized by intellectual disability, liver malfunctioning, muscular hypotonia, involuntary movements, and decreased or absent tear production. Liver biopsy demonstrates vacuolar amorphous cytoplasmic storage material. NGLY1 deficiency is caused by bi-allelic variants in NGLY1 which catalyzes protein deglycosylation. We describe five patients from two families with NGLY1 deficiency due to homozygosity for two novel NGLY1 variants, and compare their findings to those of earlier reported patients. The typical features of the disorder are present in a limited way, and there is intra-familial variability. In addition in one of the families the muscle atrophy and posture abnormalities are marked. These can be explained either as variability of the phenotype or as sign of slowly progression of features as the present affected individuals are older than earlier reported patients.
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http://dx.doi.org/10.1016/j.ejmg.2021.104146DOI Listing
March 2021

Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.

Hum Mol Genet 2021 03;30(1):72-77

Department of Medical Genetics, Haukeland University Hospital, Bergen 5021, Norway.

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are otherwise healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggests that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.
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http://dx.doi.org/10.1093/hmg/ddab014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033145PMC
March 2021

Genetic control of tumor development in malformation syndromes.

Am J Med Genet A 2021 02 3;185(2):324-335. Epub 2020 Nov 3.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

One of the questions that arises frequently when caring for an individual with a malformation syndrome, is whether some form of tumor surveillance is indicated. In some syndromes there is a highly variable increased risk to develop tumors, while in others this is not the case. The risks can be hard to predict and difficult to explain to affected individuals and their families, and often also to caregivers. The queries arise especially if syndrome causing mutations are also known to occur in tumors. It needs insight in the mechanisms to understand and explain differences of tumor occurrence, and to offer optimal care to individuals with syndromes. Here we provide a short overview of the major mechanisms of the control for tumor occurrences in malformation syndromes.
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http://dx.doi.org/10.1002/ajmg.a.61947DOI Listing
February 2021

DOORS syndrome and a recurrent truncating ATP6V1B2 variant.

Genet Med 2021 01 2;23(1):149-154. Epub 2020 Sep 2.

Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada.

Purpose: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant.

Methods: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants.

Results: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found.

Conclusion: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.
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http://dx.doi.org/10.1038/s41436-020-00950-9DOI Listing
January 2021

Pathophysiology of premature aging characteristics in Mendelian progeroid disorders.

Eur J Med Genet 2020 Nov 10;63(11):104028. Epub 2020 Aug 10.

Department of Paediatrics, Room H7-236, Amsterdam UMC - location AMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. Electronic address:

Aging is a physiological process that is in part genetically determined. Some of the signs and symptoms of aging also occur prematurely in Mendelian disorders. Such disorders are excellent sources of information of underlying mechanisms for these components of aging, and studying these may allow detection of pathways that have not yet considered in detail in physiological aging. Here I define the clinical characteristics that constitute aging and propose that at least 40% of aging signs and symptoms should be present before an entity should be tagged as progeroid. A literature search using these characteristics yields 17 entities that fulfill this definition: Hutchinson-Gilford progeria, mandibulo-acral dysplasia, Nestor-Guillermo progeria, Werner syndrome, Cockayne syndrome, cutis laxa progeroid, Penttinen progeroid syndrome, Mandibular underdevelopment, Deafness, Progeroid features, Lipodystrophy, Fontaine progeroid syndrome, SHORT syndrome, Wiedemann-Rautenstrauch syndrome, Mulvihill-Smith syndrome, dyskeratosis congenita, Marfan syndrome lipodystrophy type, Warburg-Cinotti syndrome, Lessel syndrome and Bloom syndrome. The presenting and main characteristics of these entities are indicated briefly. Their pathophysiology is not complete pathophysiology is reviewed but only the pathophysiology of the premature aging characteristics of this series of entities is compared to the known mechanisms ("Hallmarks") of physiological aging as summarized in the review paper by Lopez-Otin and colleagues. Although many causative genes have not been studied fully for all known aging mechanisms the comparison demonstrates that additional mechanisms must play a role to explain the aging characteristic in some of the progeroid entities of the progeroid entities, and possibly also in physiological aging.
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http://dx.doi.org/10.1016/j.ejmg.2020.104028DOI Listing
November 2020

The external phenotype of aging.

Eur J Med Genet 2020 Nov 26;63(11):103995. Epub 2020 Jul 26.

Department of Paediatrics, Room H7-236, Amsterdam UMC - location AMC, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. Electronic address:

Aging is widely studied as a physiological process. Segmental aging can also occur prematurely in Mendelian disorders, and these can act this way as excellent sources of information, specifically for the underlying mechanisms. Adequate recognition of such aging characteristics in Mendelian disorders needs a well-defined phenotype of aging. Here the external phenotype of aging is described that can be recognized in the consulting room without major additional studies. Existing definitions of the signs and symptoms in Elements of Morphology or Human Phenotype Ontology are added or a new definition is suggested if none is available.
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http://dx.doi.org/10.1016/j.ejmg.2020.103995DOI Listing
November 2020

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.

Genet Med 2020 11 22;22(11):1838-1850. Epub 2020 Jul 22.

Department of Genetics, Robert Debré Hospital, AP-HP, Paris, France.

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.

Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.

Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.

Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.
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http://dx.doi.org/10.1038/s41436-020-0898-yDOI Listing
November 2020

Primrose syndrome: Characterization of the phenotype in 42 patients.

Clin Genet 2020 06 20;97(6):890-901. Epub 2020 Apr 20.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
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http://dx.doi.org/10.1111/cge.13749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384157PMC
June 2020

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.

Hum Genet 2020 May 19;139(5):575-592. Epub 2020 Mar 19.

Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.
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http://dx.doi.org/10.1007/s00439-020-02138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170815PMC
May 2020

A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote.

Clin Genet 2020 06 10;97(6):915-919. Epub 2020 Mar 10.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.
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http://dx.doi.org/10.1111/cge.13730DOI Listing
June 2020

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):356-370. Epub 2020 Feb 27.

Université de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058829PMC
March 2020

European lipodystrophy registry: background and structure.

Orphanet J Rare Dis 2020 01 15;15(1):17. Epub 2020 Jan 15.

Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, Centre for Rare Endocrine Disorders, Ulm University Medical Centre, Eythstraße 24, 89075, Ulm, Germany.

Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy.

Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years.

Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry.

Study Registration: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.
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http://dx.doi.org/10.1186/s13023-020-1295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964101PMC
January 2020

Variants in nuclear factor I genes influence growth and development.

Am J Med Genet C Semin Med Genet 2019 12 15;181(4):611-626. Epub 2019 Nov 15.

Department of Pediatrics, University of Amsterdam, Amsterdam, The Netherlands.

The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.
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http://dx.doi.org/10.1002/ajmg.c.31747DOI Listing
December 2019

Elements of morphology: Standard terminology for the teeth and classifying genetic dental disorders.

Am J Med Genet A 2019 10 29;179(10):1913-1981. Epub 2019 Aug 29.

Filière de santé Maladies Rares TETECOU: Malformations rares de la tête, du cou et des dents, Hôpital Necker-Enfants Malades, Paris, France.

Dental anomalies occur frequently in a number of genetic disorders and act as major signs in diagnosing these disorders. We present definitions of the most common dental signs and propose a classification usable as a diagnostic tool by dentists, clinical geneticists, and other health care providers. The definitions are part of the series Elements of Morphology and have been established after careful discussions within an international group of experienced dentists and geneticists. The classification system was elaborated in the French collaborative network "TÊTECOU" and the affiliated O-Rares reference/competence centers. The classification includes isolated and syndromic disorders with oral and dental anomalies, to which causative genes and main extraoral signs and symptoms are added. A systematic literature analysis yielded 408 entities of which a causal gene has been identified in 79%. We classified dental disorders in eight groups: dental agenesis, supernumerary teeth, dental size and/or shape, enamel, dentin, dental eruption, periodontal and gingival, and tumor-like anomalies. We aim the classification to act as a shared reference for clinical and epidemiological studies. We welcome critical evaluations of the definitions and classification and will regularly update the classification for newly recognized conditions.
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http://dx.doi.org/10.1002/ajmg.a.61316DOI Listing
October 2019

Thyroid function in males with fragile X syndrome.

J Pediatr Endocrinol Metab 2019 Aug;32(8):903-905

Department of Pediatric Endocrinology, Amsterdam University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1515/jpem-2019-0224DOI Listing
August 2019

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.

Hum Mutat 2019 12 21;40(12):2270-2285. Epub 2019 Aug 21.

Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.
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http://dx.doi.org/10.1002/humu.23841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874899PMC
December 2019

Widespread aplasia cutis congenita in sibs with PLEC1 and ITGB4 variants.

Am J Med Genet A 2019 08 11;179(8):1547-1555. Epub 2019 Jun 11.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Aplasia cutis congenita (ACC) is a heterogeneous group of disorders characterized by localized or widespread absence of skin. ACC can occur isolated or as part of a syndrome. Here we report two consanguineous families, each with two affected offspring. Affected individuals showed widespread ACC while the skin in between had a normal appearance. Ears and nose of the four patients were underdeveloped, otherwise there were no unusual physical characteristics and no internal organ anomalies. "Whole" exome sequencing (WES) of the mother of Family 1 yielded a pathogenic heterozygote variant in ITGB4. The father and healthy offspring were heterozygous for the same variant. WES of the mother of Family 2 yielded a variant in PLEC1. The father and grandmother, who had a history of two offspring with fatal ACC, were heterozygous for the same variant. PLEC1 and ITGB4 have both been previously been reported in association with ACC. We compare findings in earlier reported individuals with variants in ITGB4 and PLEC1, and provide a short summary of other entities going along with ACC.
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http://dx.doi.org/10.1002/ajmg.a.61260DOI Listing
August 2019

Multiple tumors due to mosaic genome-wide paternal uniparental disomy.

Pediatr Blood Cancer 2019 06 18;66(6):e27715. Epub 2019 Mar 18.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Mosaic genome-wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith-Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed. Genetic counseling and a life-long alertness for the development of tumors is indicated. We describe the long diagnostic process of a patient who already had a tumor at birth and developed multiple tumors in childhood and adulthood. Furthermore, we offer clues to recognize the entity.
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http://dx.doi.org/10.1002/pbc.27715DOI Listing
June 2019

Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP.

Am J Med Genet A 2019 04 8;179(4):634-638. Epub 2019 Feb 8.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato (CA), Italy.

We report here a novel de novo missense variant affecting the last amino acid of exon 30 of CREBBP [NM_004380, c.5170G>A; p.(Glu1724Lys)] in a 17-year-old boy presenting mild intellectual disability and dysmorphisms but not resembling the phenotype of classical Rubinstein-Taybi syndrome. The patient showed a marked overweight from early infancy on and had cortical heterotopias. Recently, 22 individuals have been reported with missense mutations in the last part of exon 30 and the beginning of exon 31 of CREBBP, showing this new phenotype. This additional case further delineates the genotype-phenotype correlations within the molecular and phenotypic spectrum of variants in CREBBP and EP300.
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http://dx.doi.org/10.1002/ajmg.a.61052DOI Listing
April 2019

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Clin Genet 2019 04 18;95(4):462-478. Epub 2019 Feb 18.

Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.
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http://dx.doi.org/10.1111/cge.13506DOI Listing
April 2019

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Nat Commun 2018 11 20;9(1):4885. Epub 2018 Nov 20.

Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.
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http://dx.doi.org/10.1038/s41467-018-07193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244416PMC
November 2018

Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1.

JIMD Rep 2019 23;45:65-69. Epub 2018 Oct 23.

Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry, Genetics and Pediatrics, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands.

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.
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http://dx.doi.org/10.1007/8904_2018_138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336675PMC
October 2018

Specific combinations of biallelic variants cause Wiedemann-Rautenstrauch syndrome.

J Med Genet 2018 12 15;55(12):837-846. Epub 2018 Oct 15.

Department of Paediatrics, Amsterdam UMC - location AMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause.

Methods: We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants.

Results: Biallelic variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function.

Conclusion: Biallelic mutations in , which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.
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http://dx.doi.org/10.1136/jmedgenet-2018-105528DOI Listing
December 2018

Objectifying Micrognathia Using Three-Dimensional Photogrammetric Analysis.

J Craniofac Surg 2018 Nov;29(8):2106-2109

Big Data Institute and Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford.

Background: Micrognathia occurs isolated and as part of entities like Robin sequence (RS). An objective measurement of mandible size and growth is needed to determine the degree of micrognathia and enable a comparison of treatment outcomes. A pilot study was conducted to investigate the usability of 3-dimensional (3D) facial photogrammetry, a fast, noninvasive method, to estimate mandible size and growth in a small cohort of newborns and infants.

Methods: Exterior mandibular volume was estimated using a tetrahedron defined by 4 facial landmarks. Twelve patients with RS with different etiologies were selected and photogrammetric images were obtained prospectively in 3 patients with RS in whom mandibular growth in the first year of life was determined. We used 3 tetrahedra defined by 6 landmarks on mandibular computed tomography (CT) scans to estimate an interior mandibular volume, which we compared to the exterior mandibular volume in 10 patients.

Results: The exterior mandibular volume using 3D photography could be determined in all patients. Signature heat maps allowed visualization of facial dysmorphism in 3D; signature graphs demonstrated similarities of facial dysmorphism in patients with the same etiology and differences from those with other diagnoses and from controls. The correlation between interior (3D photogrammetry) and exterior mandibular volumes (CT imaging) was 0.8789.

Conclusion: The 3D facial photogrammetry delineates the general facial characteristics in patients with different syndromes involving micrognathia, and can objectively estimate mandibular volume and growth, with excellent correlation with bony measurement. It has been concluded that 3D facial photogrammetry could be a clinically effective instrument for delineating and quantifying micrognathia.
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http://dx.doi.org/10.1097/SCS.0000000000005056DOI Listing
November 2018

Development, behaviour and autism in individuals with SMC1A variants.

J Child Psychol Psychiatry 2019 03 8;60(3):305-313. Epub 2018 Oct 8.

Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.

Introduction: Development and behaviour in Cornelia de Lange Syndrome (CdLS), including autism characteristics, have been described infrequently stratified to genetic cause and only a few studies have considered behavioural characteristics in relation to developmental level. Here, we describe the behavioural phenotype in individuals with CdLS with SMC1A variants.

Methods: We performed an international, interdisciplinary study on 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome and with Autism Spectrum Disorder. Results on cognition and self-injurious behaviour (SIB) are compared to those in individuals with CdLS caused by NIPBL variants. For Dutch participants with SMC1A variants we performed direct in-person assessments of cognition, autism, and added an interview and questionnaire on adaptive behaviour and sensory processing.

Results: Individuals with SMC1A variants show a higher cognitive level and less SIB than individuals with NIPBL variants. Individuals with SMC1A variants without classic CdLS phenotype but with a Rett-like phenotype show more severe intellectual disability and more SIB compared to those with a CdLS phenotype. Autism is less present if outcomes in direct in-person assessments are evaluated taking developmental level into account compared to results based on a questionnaire.

Conclusions: Behaviour in individuals with CdLS should be evaluated taking genetic cause into account. Detailed interdisciplinary approaches are of clinical importance to inform tailored care and may eventually improve quality of life of patients and families.
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http://dx.doi.org/10.1111/jcpp.12979DOI Listing
March 2019
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