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12 results on '"Martinez-Agosto, J.A."'

1. Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Author

Wojcik, M.H., Srivastava, S., Agrawal, P.B., Balci, T.B., Callewaert, B., Calvo, P.L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C.A., Grange, D.K., Hickey, S.E., Isidor, B., Küry, S., Lachman, H.M., Lavillaureix, A., Lyons, M.J., Marcelis, C.L.M., Marco, E.J., Martinez-Agosto, J.A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E.J., Riberi, E., Rush, E.T., Russell, B.E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D.M., Wilson, K., Jansen, S, Vries, B.B.A. de, Curry, C.J., Wojcik, M.H., Srivastava, S., Agrawal, P.B., Balci, T.B., Callewaert, B., Calvo, P.L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C.A., Grange, D.K., Hickey, S.E., Isidor, B., Küry, S., Lachman, H.M., Lavillaureix, A., Lyons, M.J., Marcelis, C.L.M., Marco, E.J., Martinez-Agosto, J.A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E.J., Riberi, E., Rush, E.T., Russell, B.E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D.M., Wilson, K., Jansen, S, Vries, B.B.A. de, and Curry, C.J.

Abstract

01 juli 2023, Item does not contain fulltext, Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Published
2023

2. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

Author

Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., Vasileiou, G., Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., and Vasileiou, G.

Abstract

Contains fulltext : 299984.pdf (Publisher’s version ) (Open Access), PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., 01 november 2023

Published
2023

3. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Author

Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.

Abstract

Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog

Published
2022

4. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Author

Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.

Abstract

Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog

Published
2022

5. Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., Lessel, D., Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., and Lessel, D.

Abstract

Contains fulltext : 245060.pdf (Publisher’s version ) (Open Access), BACKGROUND: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. METHODS: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. RESULTS: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient

Published
2021

6. Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., Lessel, D., Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., and Lessel, D.

Abstract

Contains fulltext : 245060.pdf (Publisher’s version ) (Open Access), BACKGROUND: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. METHODS: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. RESULTS: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient

Published
2021

7. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author

Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), Bhoj, E.J. (Elizabeth J.), Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), and Bhoj, E.J. (Elizabeth J.)

Abstract

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

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

Author

Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, Zweier, C., Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, and Zweier, C.

Abstract

Contains fulltext : 215582.pdf (publisher's version ) (Open Access), 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

9. Phenotype delineation of ZNF462 related syndrome

Author

Kruszka, P., Hu, T., Hong, S., Signer, R., Cogne, B., Isidor, B., Mazzola, S.E., Giltay, J.C., Gassen, K.L.I. van, England, E.M., Pais, L., Ockeloen, C.W., Sanchez-Lara, P.A., Kinning, E., Adams, D.J., Treat, K., Torres-Martinez, W., Bedeschi, M.F., Iascone, M., Blaney, S., Bell, O., Tan, T.Y., Delrue, M.A., Jurgens, J., Barry, B.J., Engle, E.C., Savage, S.K., Fleischer, N., Martinez-Agosto, J.A., Boycott, K., Zackai, E.H., Muenke, M., Kruszka, P., Hu, T., Hong, S., Signer, R., Cogne, B., Isidor, B., Mazzola, S.E., Giltay, J.C., Gassen, K.L.I. van, England, E.M., Pais, L., Ockeloen, C.W., Sanchez-Lara, P.A., Kinning, E., Adams, D.J., Treat, K., Torres-Martinez, W., Bedeschi, M.F., Iascone, M., Blaney, S., Bell, O., Tan, T.Y., Delrue, M.A., Jurgens, J., Barry, B.J., Engle, E.C., Savage, S.K., Fleischer, N., Martinez-Agosto, J.A., Boycott, K., Zackai, E.H., and Muenke, M.

Abstract

Contains fulltext : 208539.pdf (publisher's version ) (Closed access), Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

Published
2019

10. 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
Full Text
View/download PDF

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

Author

Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, Zweier, C., Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, and Zweier, C.

Abstract

Contains fulltext : 215582.pdf (publisher's version ) (Open Access), 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

12. Phenotype delineation of ZNF462 related syndrome

Author

Kruszka, P., Hu, T., Hong, S., Signer, R., Cogne, B., Isidor, B., Mazzola, S.E., Giltay, J.C., Gassen, K.L.I. van, England, E.M., Pais, L., Ockeloen, C.W., Sanchez-Lara, P.A., Kinning, E., Adams, D.J., Treat, K., Torres-Martinez, W., Bedeschi, M.F., Iascone, M., Blaney, S., Bell, O., Tan, T.Y., Delrue, M.A., Jurgens, J., Barry, B.J., Engle, E.C., Savage, S.K., Fleischer, N., Martinez-Agosto, J.A., Boycott, K., Zackai, E.H., Muenke, M., Kruszka, P., Hu, T., Hong, S., Signer, R., Cogne, B., Isidor, B., Mazzola, S.E., Giltay, J.C., Gassen, K.L.I. van, England, E.M., Pais, L., Ockeloen, C.W., Sanchez-Lara, P.A., Kinning, E., Adams, D.J., Treat, K., Torres-Martinez, W., Bedeschi, M.F., Iascone, M., Blaney, S., Bell, O., Tan, T.Y., Delrue, M.A., Jurgens, J., Barry, B.J., Engle, E.C., Savage, S.K., Fleischer, N., Martinez-Agosto, J.A., Boycott, K., Zackai, E.H., and Muenke, M.

Abstract

Contains fulltext : 208539.pdf (publisher's version ) (Closed access), Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

Published
2019

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