Marjolijn C.J. Jongmans
Radboud University Nijmegen
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Featured researches published by Marjolijn C.J. Jongmans.
Journal of Medical Genetics | 2005
Marjolijn C.J. Jongmans; Ronald J.C. Admiraal; K van der Donk; Lisenka E.L.M. Vissers; A F Baas; Livia Kapusta; J M van Hagen; Dian Donnai; T. de Ravel; Joris A. Veltman; A. Geurts van Kessel; B. de Vries; Han G. Brunner; Lies H. Hoefsloot; C.M.A. van Ravenswaaij
Background: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. Methods: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. Results: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. Conclusions:CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.
European Journal of Medical Genetics | 2009
Emilia K. Bijlsma; Antoinet C.J. Gijsbers; J.H.M. Schuurs-Hoeijmakers; A. van Haeringen; D. E. Fransen Van De Putte; Britt-Marie Anderlid; Johanna Lundin; Pablo Lapunzina; L.A. Pérez Jurado; B. Delle Chiaie; Bart Loeys; Björn Menten; A. Oostra; Helene Verhelst; David J. Amor; Damien L. Bruno; A.J. van Essen; Roel Hordijk; Birgit Sikkema-Raddatz; K.T. Verbruggen; Marjolijn C.J. Jongmans; Rolph Pfundt; H.M. Reeser; Martijn H. Breuning; Claudia Ruivenkamp
Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype.
Journal of Medical Genetics | 2011
Jorieke E. H. Bergman; N Janssen; Lies H. Hoefsloot; Marjolijn C.J. Jongmans; Robert M. W. Hofstra; C.M.A. van Ravenswaaij-Arts
Background CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene. Objective To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum. Methods We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations. Results We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome. Conclusion CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.
Nature Genetics | 2015
Robbert D.A. Weren; Marjolijn J. L. Ligtenberg; C. Marleen Kets; Richarda M. de Voer; Eugène T P Verwiel; Liesbeth Spruijt; Wendy A. G. van Zelst-Stams; Marjolijn C.J. Jongmans; Christian Gilissen; Jayne Y. Hehir-Kwa; Alexander Hoischen; Jay Shendure; Evan A. Boyle; Eveline J. Kamping; Iris D. Nagtegaal; Bastiaan Tops; Fokko M. Nagengast; Ad Geurts van Kessel; J. Han van Krieken; Roland P. Kuiper; Nicoline Hoogerbrugge
The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
American Journal of Medical Genetics Part A | 2005
Marjolijn C.J. Jongmans; Erik A. Sistermans; Alwin Rikken; Willy M. Nillesen; Rienk Tamminga; Michael A. Patton; Esther M. Maier; Marco Tartaglia; Kees Noordam; Ineke van der Burgt
Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, minor facial anomalies, and congenital heart defects. In approximately 50% of cases the condition is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the protein SHP‐2. In this study, PTPN11 mutation analysis was performed in 170 NS patients. In 76 (45%) of them a mutation was identified. We report on the distribution of these mutations, as well as on genotype–phenotype relationships. The benefit of the NS scoring system developed by van der Burgt et al. [( 1994 ); Am J Med Genet 53:187–191] is shown, among physicians who consequently based their diagnosis on the NS scoring system the percentage mutation positive subjects was 54%, whereas this percentage was only 39% among physicians who made less use of the scoring system. In two patients with some uncommon manifestations mutations were found in the C‐SH2 domain, a region in which defects are not often identified in NS. A trend was observed in patients carrying the 922A → G change (Asn308Asp) receiving normal education. In one patient with NS and mild juvenile myelomonocytic leukemia (JMML) the mutation 218C → T (Thr73Ile) was found. This confirms previous findings indicating that individuals with NS with specific mutations in PTPN11 are at risk of developing JMML.
Human Mutation | 2013
Gijs W.E. Santen; Emmelien Aten; Anneke T. Vulto-van Silfhout; Caroline Pottinger; Bregje W.M. Bon; Ivonne J.H.M. Minderhout; Ronelle Snowdowne; Christian A.C. Lans; Merel W. Boogaard; Margot M.L. Linssen; Linda Vijfhuizen; Michiel J.R. Wielen; M.J. (Ellen) Vollebregt; Martijn H. Breuning; Marjolein Kriek; Arie van Haeringen; Johan T. den Dunnen; Alexander Hoischen; Jill Clayton-Smith; Bert B.A. Vries; Raoul C. M. Hennekam; Martine J. van Belzen; Mariam Almureikhi; Anwar Baban; Mafalda Barbosa; Tawfeg Ben-Omran; Katherine Berry; Stefania Bigoni; Odile Boute; Louise Brueton
De novo germline variants in several components of the SWI/SNF‐like BAF complex can cause Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD‐powered databases to facilitate further genotype–phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype–genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.
American Journal of Medical Genetics Part A | 2008
Marjolijn C.J. Jongmans; Lies H. Hoefsloot; Kim P. van der Donk; Ronald J.C. Admiraal; Alex Magee; Ingrid van de Laar; Yvonne Hendriks; Joke B. G. M. Verheij; Ian Walpole; Han G. Brunner; Conny van Ravenswaaij
CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features. We observed somatic and germline mosaicism as well as parent‐to‐child transmission of non‐mosaic CHD7 mutations as causes of familial CHARGE syndrome. In one family with two affected sibs a somatic mutation was identified in lymphocytes of a clinically unaffected parent (2520G > A in exon 8). This is the second report of somatic CHD7 mosaicism in an unaffected parent. In two further families with affected siblings, we could not detect the mutation in parental lymphocytes suggesting germline mosaicism. The previously reported clinical variability was strikingly present in all five families. We find that alterations in CHD7 can result in a very mild phenotype, characterized by only a few minor symptoms of the CHARGE syndrome clinical spectrum. Such a mild phenotype was present in two families that shared the same 6322G > A missense mutation. These two families showed parent‐to‐child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members.
European Journal of Human Genetics | 2011
Marjolijn C.J. Jongmans; Ineke van der Burgt; Peter M. Hoogerbrugge; Kees Noordam; Helger G. Yntema; Willy M. Nillesen; Roland P. Kuiper; Marjolijn J. L. Ligtenberg; Ad Geurts van Kessel; J. Han van Krieken; Lambertus A. Kiemeney; Nicoline Hoogerbrugge
Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8–38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0–5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance.
Journal of Medical Genetics | 2015
Maxime G. Blanchard; Marjolein H. Willemsen; Jaclyn B. Walker; Sulayman D. Dib-Hajj; Stephen G. Waxman; Marjolijn C.J. Jongmans; Tjitske Kleefstra; Bart P. van de Warrenburg; Peter Praamstra; Joost Nicolai; Helger G. Yntema; René J. M. Bindels; Miriam H. Meisler; Erik Jan Kamsteeg
Background Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. Methods The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype–phenotype correlations of these and other cases were related to the functional analyses. Results The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. Conclusions Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.
Acta Neuropathologica | 2014
Leanne de Kock; Nelly Sabbaghian; Harriet Druker; Evan Weber; Nancy Hamel; Suzanne Miller; Catherine S. Choong; Nicholas G. Gottardo; Ursula R. Kees; Surya P. Rednam; Liselotte P. van Hest; Marjolijn C.J. Jongmans; Shalini N. Jhangiani; James R. Lupski; Margaret Zacharin; Dorothée Bouron-Dal Soglio; Annie Huang; John R. Priest; Arie Perry; Sabine Mueller; Steffen Albrecht; David Malkin; Richard Grundy; William D. Foulkes
Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.