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16 results on '"Pfundt, R. (Rolph)"'

1. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Balasubramanian, M. (Meena), Dingemans, A.J.M. (Alexander J. M.), Albaba, S. (Shadi), Richardson, R. (Ruth), Yates, T.M. (Thabo M.), Cox, H. (H.), Douzgou, S. (Sofia), Armstrong, R. (Ruth), Sansbury, F.H. (Francis H.), Burke, K.B. (Katherine B.), Fry, A.E. (Andrew E.), Ragge, N. (Nicola), Sharif, S. (Saba), Foster, A. (Alison), Sandre-Giovannoli, A. (Annachiara) de, Elouej, S. (Sahar), Vasudevan, P. (Pradeep), Mansour, S. (Sahar), Wilson, K. (Kate), Stewart, H. (Helen), Heide, S. (Solveig), Nava, C. (Caroline), Keren, B. (Boris), Demirdas, S. (Serwet), Brooks, A.S. (Alice S.), Vincent, M. (Marie), Isidor, B. (Bertrand), Küry, S. (Sebastien), Schouten, M. (Meyke), Leenders, E. (Erika), Chung, W. (Wendy), Haeringen, A. (Arie van), Scheffner, T. (Thomas), Debray, F.-G. (Francois-Guillaume), White, S.M. (Susan M.), Palafoll, M.I.V. (Maria Irene Valenzuela), Pfundt, R. (Rolph), Newbury-Ecob, R. (Ruth), Kleefstra, T. (Tjitske), Balasubramanian, M. (Meena), Dingemans, A.J.M. (Alexander J. M.), Albaba, S. (Shadi), Richardson, R. (Ruth), Yates, T.M. (Thabo M.), Cox, H. (H.), Douzgou, S. (Sofia), Armstrong, R. (Ruth), Sansbury, F.H. (Francis H.), Burke, K.B. (Katherine B.), Fry, A.E. (Andrew E.), Ragge, N. (Nicola), Sharif, S. (Saba), Foster, A. (Alison), Sandre-Giovannoli, A. (Annachiara) de, Elouej, S. (Sahar), Vasudevan, P. (Pradeep), Mansour, S. (Sahar), Wilson, K. (Kate), Stewart, H. (Helen), Heide, S. (Solveig), Nava, C. (Caroline), Keren, B. (Boris), Demirdas, S. (Serwet), Brooks, A.S. (Alice S.), Vincent, M. (Marie), Isidor, B. (Bertrand), Küry, S. (Sebastien), Schouten, M. (Meyke), Leenders, E. (Erika), Chung, W. (Wendy), Haeringen, A. (Arie van), Scheffner, T. (Thomas), Debray, F.-G. (Francois-Guillaume), White, S.M. (Susan M.), Palafoll, M.I.V. (Maria Irene Valenzuela), Pfundt, R. (Rolph), Newbury-Ecob, R. (Ruth), and Kleefstra, T. (Tjitske)

Abstract

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

Published
2021
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2. A de novo CTNNB1 Novel Splice Variant in an Adult Female with Severe Intellectual Disability

Author

Verhoeven, W.M.A., Egger, J.I.M. (Jos), Jongbloed, R.E., van Putten, M.M., de Bruijn-van Zandwijk, M., Zwemer, A.S., Pfundt, R. (Rolph), Willemsen, M.H. (Marjolein), Verhoeven, W.M.A., Egger, J.I.M. (Jos), Jongbloed, R.E., van Putten, M.M., de Bruijn-van Zandwijk, M., Zwemer, A.S., Pfundt, R. (Rolph), and Willemsen, M.H. (Marjolein)

Abstract

The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27–51 years), while the majority was infant or adolescent (range: 0–20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.

Published
2020
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3. Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging

Author

Deden, C. (Chantal), Neveling, K. (Kornelia), Zafeiropopoulou, D. (Dimitra), Gilissen, C. (Christian), Pfundt, R. (Rolph), Rinne, T. (Tuula), Leeuw, N. (Nicole) de, Faas, B.H.W. (Brigitte), Gardeitchik, T. (Thatjana), Sallevelt, S.C.E.H. (Suzanne), Paulussen, A.D.C. (Aimée), Stevens, S.J.C. (Servi J. C.), Sikkel, E. (Esther), Elting, M. (Mariet), Maarle, M.C. (Merel), Diderich, K.E.M. (Karin), Corsten-Janssen, N. (Nicole), Lichtenbelt, K.D. (Klaske), Lachmeijer, G. (Guus), Vissers, L.E.L.M., Yntema, H.G., Nelen, M. (Marcel), Feenstra, I. (Ilse), Zelst-Stams, W.A. van, Deden, C. (Chantal), Neveling, K. (Kornelia), Zafeiropopoulou, D. (Dimitra), Gilissen, C. (Christian), Pfundt, R. (Rolph), Rinne, T. (Tuula), Leeuw, N. (Nicole) de, Faas, B.H.W. (Brigitte), Gardeitchik, T. (Thatjana), Sallevelt, S.C.E.H. (Suzanne), Paulussen, A.D.C. (Aimée), Stevens, S.J.C. (Servi J. C.), Sikkel, E. (Esther), Elting, M. (Mariet), Maarle, M.C. (Merel), Diderich, K.E.M. (Karin), Corsten-Janssen, N. (Nicole), Lichtenbelt, K.D. (Klaske), Lachmeijer, G. (Guus), Vissers, L.E.L.M., Yntema, H.G., Nelen, M. (Marcel), Feenstra, I. (Ilse), and Zelst-Stams, W.A. van

Abstract

Objective: The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging. Methods: In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7). Results: A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases. Conclusions: These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.

Published
2020
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4. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Author

Hengel, H. (Holger), Bosso-Lefèvre, C. (Célia), Grady, G. (George), Szenker-Ravi, E. (Emmanuelle), Li, H. (Hankun), Pierce, S. (Sarah), Lebigot, É. (Élise), Tan, T.-T. (Thong-Teck), Eio, M.Y. (Michelle Y.), Narayanan, G. (Gunaseelan), Utami, K.H. (Kagistia Hana), Yau, M. (Monica), Handal, N. (Nader), Deigendesch, W. (Werner), Keimer, R. (Reinhard), Marzouqa, H.M. (Hiyam M.), Gunay-Aygun, M. (Meral), Muriello, M.J. (Michael J.), Verhelst, H. (H.), Weckhuysen, S. (Sarah), Mahida, S. (Sonal), Naidu, S. (Sakkubai), Thomas, T.G. (Terrence G.), Lim, J.Y. (Jiin Ying), Tan, E.S. (Ee Shien), Haye, D. (Damien), Willemsen, M.A. (Michél), Oegema, R. (Renske), Mitchell, W.G. (Wendy G.), Pierson, T.M. (Tyler Mark), Andrews, M.V. (Marisa V.), Willing, M.C. (Marcia C.), Rodan, L.H. (Lance H.), Barakat, T.S. (Tahsin Stefan), Slegtenhorst, M.A. (Marjon) van, Gavrilova, R.H. (Ralitza H.), Martinelli, D. (Diego), Gilboa, T. (Tal), Tamim, A.M. (Abdullah M.), Hashem, M.O. (Mais O.), AlSayed, M.D. (Moeenaldeen D.), Abdulrahim, M.M. (Maha M.), Al-Owain, M. (Mohammed), Awaji, A. (Ali), Mahmoud, A.A.H. (Adel A. H.), Faqeih, E.A. (Eissa A.), Asmari, A.A. (Ali Al), Algain, S.M. (Sulwan M.), Jad, L.A. (Lamyaa A.), Aldhalaan, H.M. (Hesham M.), Helbig, I. (Ingo), Koolen, D.A. (David), Rieß, A. (Angelika), Kraegeloh-Mann, I. (Ingeborg), Bauer, P. (Peter), Gulsuner, S. (Suleyman), Stamberger, H. (Hannah), Ng, A.Y.J. (Alvin Yu Jin), Tang, S. (Sha), Tohari, S. (Sumanty), Keren, B. (Boris), Schultz-Rogers, L.E. (Laura E.), Klee, E.W. (Eric W.), Barresi, S. (Sabina), Tartaglia, M. (Marco), Mor-Shaked, H. (Hagar), Maddirevula, S. (Sateesh), Begtrup, A. (Amber), Telegrafi, A. (Aida), Pfundt, R. (Rolph), Schüle, R. (Rebecca), Ciruna, B. (Brian), Bonnard, C. (Carine), Pouladi, M.A. (Mahmoud A.), Stewart, J.C. (James C.), Claridge-Chang, A. (Adam), Lefeber, D.J. (Dirk J.), Alkuraya, F.S. (Fowzan S), Mathuru, A.S. (Ajay S.), Venkatesh, B. (Byrappa), Barycki, J.J. (Joseph J.), Simpson, M.A. (Melanie A.), Jamuar, S.S. (Saumya S.), Schöls, L. (Ludger), Reversade, B. (Bruno), Hengel, H. (Holger), Bosso-Lefèvre, C. (Célia), Grady, G. (George), Szenker-Ravi, E. (Emmanuelle), Li, H. (Hankun), Pierce, S. (Sarah), Lebigot, É. (Élise), Tan, T.-T. (Thong-Teck), Eio, M.Y. (Michelle Y.), Narayanan, G. (Gunaseelan), Utami, K.H. (Kagistia Hana), Yau, M. (Monica), Handal, N. (Nader), Deigendesch, W. (Werner), Keimer, R. (Reinhard), Marzouqa, H.M. (Hiyam M.), Gunay-Aygun, M. (Meral), Muriello, M.J. (Michael J.), Verhelst, H. (H.), Weckhuysen, S. (Sarah), Mahida, S. (Sonal), Naidu, S. (Sakkubai), Thomas, T.G. (Terrence G.), Lim, J.Y. (Jiin Ying), Tan, E.S. (Ee Shien), Haye, D. (Damien), Willemsen, M.A. (Michél), Oegema, R. (Renske), Mitchell, W.G. (Wendy G.), Pierson, T.M. (Tyler Mark), Andrews, M.V. (Marisa V.), Willing, M.C. (Marcia C.), Rodan, L.H. (Lance H.), Barakat, T.S. (Tahsin Stefan), Slegtenhorst, M.A. (Marjon) van, Gavrilova, R.H. (Ralitza H.), Martinelli, D. (Diego), Gilboa, T. (Tal), Tamim, A.M. (Abdullah M.), Hashem, M.O. (Mais O.), AlSayed, M.D. (Moeenaldeen D.), Abdulrahim, M.M. (Maha M.), Al-Owain, M. (Mohammed), Awaji, A. (Ali), Mahmoud, A.A.H. (Adel A. H.), Faqeih, E.A. (Eissa A.), Asmari, A.A. (Ali Al), Algain, S.M. (Sulwan M.), Jad, L.A. (Lamyaa A.), Aldhalaan, H.M. (Hesham M.), Helbig, I. (Ingo), Koolen, D.A. (David), Rieß, A. (Angelika), Kraegeloh-Mann, I. (Ingeborg), Bauer, P. (Peter), Gulsuner, S. (Suleyman), Stamberger, H. (Hannah), Ng, A.Y.J. (Alvin Yu Jin), Tang, S. (Sha), Tohari, S. (Sumanty), Keren, B. (Boris), Schultz-Rogers, L.E. (Laura E.), Klee, E.W. (Eric W.), Barresi, S. (Sabina), Tartaglia, M. (Marco), Mor-Shaked, H. (Hagar), Maddirevula, S. (Sateesh), Begtrup, A. (Amber), Telegrafi, A. (Aida), Pfundt, R. (Rolph), Schüle, R. (Rebecca), Ciruna, B. (Brian), Bonnard, C. (Carine), Pouladi, M.A. (Mahmoud A.), Stewart, J.C. (James C.), Claridge-Chang, A. (Adam), Lefeber, D.J. (Dirk J.), Alkuraya, F.S. (Fowzan S), Mathuru, A.S. (Ajay S.), Venkatesh, B. (Byrappa), Barycki, J.J. (Joseph J.), Simpson, M.A. (Melanie A.), Jamuar, S.S. (Saumya S.), Schöls, L. (Ludger), and Reversade, B. (Bruno)

Abstract

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Published
2020
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5. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E. D. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S. L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K. E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M. H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H. M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P. R. (Patrick R.), Ellingson, M. S. (Marissa S.), Ferber, M. J. (Matthew J.), Dhamija, R. (Radhika), Klee, E. W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K. D. (Klaske D.), Kenney, A. (Amy), Vergano, S. A. (Samantha A.), Jamra, R. A. (Rami Abou), Platzer, K. (Konrad), Pierpont, M. E. (Mary Ella), Khattar, D. (Divya), Hopkin, R. J. (Robert J.), Martin, R. J. (Richard J.), Jongmans, M. C. (Marjolijn C. J.), Chang, V. Y. (Vivian Y.), Martinez-Agosto, J. A. (Julian A.), Kuismin, O. (Outi), Kurki, M. I. (Mitja I.), Pietiläinen, O. (Olli), Palotie, A. (Aarno), Maarup, T. J. (Timothy J.), Johnson, D. S. (Diana S.), Venborg Pedersen, K. (Katja), Laulund, L. W. (Lone W.), Lynch, S. A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E. H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Study, D. (DDD), Sticht, H. (Heinrich), Gregor, A. (Anne), Van Esch, H. (Hilde), and Zweier, C. (Christiane)

Subjects
Drosophila melanogaster, intellectual disability, neurodevelopmental disorders, CTCF, chromatin organization
Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019

6. Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data

Author

Fokkema, I., Velde, K. (KJoeri) van der, Slofstra, M.K., Ruivenkamp, C.A. (Claudia), Vogel, M.J. (Maartje), Pfundt, R. (Rolph), Blok, M.J.C., Deprez, R.H.L., Waisfisz, Q. (Quinten), Abbott, K.M. (Kristin), Sinke, R.J. (Richard), Rahman, R. (Rosanna), Nijman, I.J. (Isaac ), Koning, B.A.E. (Barbara) de, Thijs, G., Wieskamp, N., Moritz, R.J.G., Charbon, B., Saris, J.J. (Jasper), Dunnen, J.T. (Johan) den, Laros, J.F.J. (Jeroen F.), Bakker, P.I.W. (Paul) de, Gijn, M. (Marielle) van, Fokkema, I., Velde, K. (KJoeri) van der, Slofstra, M.K., Ruivenkamp, C.A. (Claudia), Vogel, M.J. (Maartje), Pfundt, R. (Rolph), Blok, M.J.C., Deprez, R.H.L., Waisfisz, Q. (Quinten), Abbott, K.M. (Kristin), Sinke, R.J. (Richard), Rahman, R. (Rosanna), Nijman, I.J. (Isaac ), Koning, B.A.E. (Barbara) de, Thijs, G., Wieskamp, N., Moritz, R.J.G., Charbon, B., Saris, J.J. (Jasper), Dunnen, J.T. (Johan) den, Laros, J.F.J. (Jeroen F.), Bakker, P.I.W. (Paul) de, and Gijn, M. (Marielle) van

Abstract

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next‐generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5‐tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as “consensus” w

Published
2019
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7. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, Zweier, C. (Christiane), Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, and Zweier, C. (Christiane)

Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019
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8. A novel MBD5 mutation in an intellectually disabled adult female patient with epilepsy: Suggestive of early onset dementia?

Author

Verhoeven, W.M.A. (Wim), Egger, J.I.M. (Jos), Kipp, J. (Janneke), Verheul- aan de Wiel, J. (Jiska), Ockeloen, C. (Charlotte), Kleefstra, T. (Tjitske), Pfundt, R. (Rolph), Verhoeven, W.M.A. (Wim), Egger, J.I.M. (Jos), Kipp, J. (Janneke), Verheul- aan de Wiel, J. (Jiska), Ockeloen, C. (Charlotte), Kleefstra, T. (Tjitske), and Pfundt, R. (Rolph)

Abstract

Background: The minimal critical region in 2q23.1 deletion syndrome comprises one gene only, that is, the methyl-CpG-binding domain protein 5 (MBD5) gene. Since the phenotypes of patients with deletions, duplications or pathogenic variants of MBD5 show considerable overlap, the term MBD5-associated neurodevelopmental disorder (MAND) was proposed. These syndromes are characterized by intellectual disability, seizures of any kind and symptoms from the autism spectrum. In a very limited number of patients, MAND may be associated with regression starting either at early infancy or at midlife. Methods: The present paper describes a severely intellectually disabled autistic female with therapy resistant complex partial epilepsy starting at her 16the with gradual cognitive and behavioral regression towards her sixth decade. Results: Cognitive and behavioral regression occurred towards the patient's sixth decade. Exome sequencing disclosed a novel heterozygous pathogenic frameshift mutation of MBD5 that was considered to be causative for the combination of intellectual disability, treatment-resistant epilepsy and autism. Conclusion: The presented patient is the second with a pathogenic MBD5 mutation in whom the course of disease is suggestive of early onset dementia starting in her fifth decade. These findings stress the importance of exome sequencing, also in elderly intellectually disabled patients, particularly in those with autism.

Published
2019
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9. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., Santen, G.W.E. (Gijs), van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., and Santen, G.W.E. (Gijs)

Abstract

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Published
2018
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10. The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands

Author

Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), Yntema, H.G., Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), and Yntema, H.G.

Abstract

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Published
2017
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11. Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Author

Haer-Wigman, L. (Lonneke), Zelst-Stams, W.A. van, Pfundt, R. (Rolph), Born, L.I. (Ingeborgh) van den, Klaver, C.C.W. (Caroline), Verheij, J.B. (Joke), Hoyng, C.B. (Carel), Breuning, M.H. (Martijn), Boon, C.J.F. (Camiel), Kievit, A.J.A. (Anneke J.A.), Verhoeven, V.J.M. (Virginie), Pott, J.W.R., Sallevelt, S.C.E.H. (Suzanne), Hagen, J.M. (Johanna) van, Plomp, A. (Astrid), Kroes, H.Y. (Hester), Lelieveld, S.H. (Stefan H.), Hehir-Kwa, J. (Jayne), Castelein, S. (Steven), Nelen, M.R. (Marcel), Scheffer, H. (Hans), Lugtenberg, D. (Dorien), Cremers, F.P.M. (Frans), Hoefsloot, E.H. (Lies), Yntema, H.G., Haer-Wigman, L. (Lonneke), Zelst-Stams, W.A. van, Pfundt, R. (Rolph), Born, L.I. (Ingeborgh) van den, Klaver, C.C.W. (Caroline), Verheij, J.B. (Joke), Hoyng, C.B. (Carel), Breuning, M.H. (Martijn), Boon, C.J.F. (Camiel), Kievit, A.J.A. (Anneke J.A.), Verhoeven, V.J.M. (Virginie), Pott, J.W.R., Sallevelt, S.C.E.H. (Suzanne), Hagen, J.M. (Johanna) van, Plomp, A. (Astrid), Kroes, H.Y. (Hester), Lelieveld, S.H. (Stefan H.), Hehir-Kwa, J. (Jayne), Castelein, S. (Steven), Nelen, M.R. (Marcel), Scheffer, H. (Hans), Lugtenberg, D. (Dorien), Cremers, F.P.M. (Frans), Hoefsloot, E.H. (Lies), and Yntema, H.G.

Abstract

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.

Published
2017
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12. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author

Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., Vries, B. (Boukje) de, Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., and Vries, B. (Boukje) de

Abstract

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Published
2017
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13. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Author

Reijnders, M.R.F. (Margot R.F.), Ansor, N.M. (Nurhuda M.), Kousi, M. (Maria), Yue, W.W. (Wyatt W.), Tan, P.L. (Perciliz L.), Clarkson, K. (Katie), Clayton-Smith, J., Corning, K. (Ken), Jones, J.R. (Julie R.), Lam, W.W.K. (Wayne W.K.), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Mohammed, S. (Shabaz), Pfundt, R. (Rolph), Roifman, M. (Maian), Cohn, R.D., Chitayat, D. (David), Millard, T.H. (Tom H.), Katsanis, N. (Nicholas), Brunner, H.G., Banka, S. (Siddharth), Reijnders, M.R.F. (Margot R.F.), Ansor, N.M. (Nurhuda M.), Kousi, M. (Maria), Yue, W.W. (Wyatt W.), Tan, P.L. (Perciliz L.), Clarkson, K. (Katie), Clayton-Smith, J., Corning, K. (Ken), Jones, J.R. (Julie R.), Lam, W.W.K. (Wayne W.K.), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Mohammed, S. (Shabaz), Pfundt, R. (Rolph), Roifman, M. (Maian), Cohn, R.D., Chitayat, D. (David), Millard, T.H. (Tom H.), Katsanis, N. (Nicholas), Brunner, H.G., and Banka, S. (Siddharth)

Abstract

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between −2.5 to −5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

Published
2017
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14. Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Author

Reijnders, M.R.F. (Margot R.F.), Kousi, M. (M.), Woerden, G.M. (Geeske) van, Klein, M. (Marieke), Bralten, L.B.C. (Linda), Mancini, G.M.S. (Grazia), Essen, T. (Ton) van, Proietti-Onori, M. (Martina), Smeets, E.E.J. (Eric E.J.), Van Gastel, M. (M.), Stegmann, A.P.A. (A. P.A.), Stevens, S.J.C. (S. J.C.), Lelieveld, S.H. (S. H.), Gilissen, C. (Christian), Pfundt, R. (Rolph), Tan, P.L. (P. L.), Kleefstra, T. (Tjitske), Franke, B. (Barbara), Elgersma, Y. (Ype), Katsanis, N. (Nicholas), Brunner, H.G., Reijnders, M.R.F. (Margot R.F.), Kousi, M. (M.), Woerden, G.M. (Geeske) van, Klein, M. (Marieke), Bralten, L.B.C. (Linda), Mancini, G.M.S. (Grazia), Essen, T. (Ton) van, Proietti-Onori, M. (Martina), Smeets, E.E.J. (Eric E.J.), Van Gastel, M. (M.), Stegmann, A.P.A. (A. P.A.), Stevens, S.J.C. (S. J.C.), Lelieveld, S.H. (S. H.), Gilissen, C. (Christian), Pfundt, R. (Rolph), Tan, P.L. (P. L.), Kleefstra, T. (Tjitske), Franke, B. (Barbara), Elgersma, Y. (Ype), Katsanis, N. (Nicholas), and Brunner, H.G.

Abstract

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Published
2017
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15. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), Kleefstra, T. (Tjitske), Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), and Kleefstra, T. (Tjitske)

Abstract

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected

Published
2016
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16. Copy number variants in a sample of patients with psychotic disorders: Is standard screening relevant for actual clinical practice?

Author

Kerkhof, N.W.A. (Noortje) van de, Feenstra, I. (Ilse), Heijden, F.M.M.A. (Frank) van der, Leeuw, N. (Nicole) de, Pfundt, R. (Rolph), Stöber, G. (Gerald), Egger, J.I.M. (Jos), Verhoeven, W.M.A. (Wim), Kerkhof, N.W.A. (Noortje) van de, Feenstra, I. (Ilse), Heijden, F.M.M.A. (Frank) van der, Leeuw, N. (Nicole) de, Pfundt, R. (Rolph), Stöber, G. (Gerald), Egger, J.I.M. (Jos), and Verhoeven, W.M.A. (Wim)

Abstract

With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment.

Published
2012
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