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1. Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Author

Kaur, M, Blair, J, Devkota, B, Fortunato, S, Clark, D, Lawrence, A, Kim, J, Do, W, Semeo, B, Katz, O, Mehta, D, Yamamoto, N, Schindler, E, Al Rawi, Z, Wallace, N, Wilde, JJ, McCallum, J, Liu, J, Xu, D, Jackson, M, Rentas, S, Tayoun, AA, Zhe, Z, Abdul-Rahman, O, Allen, B, Angula, MA, Anyane-Yeboa, K, Argente, J, Arn, PH, Armstrong, L, Basel-Salmon, L, Baynam, G, Bird, LM, Bruegger, D, Ch'ng, G-S, Chitayat, D, Clark, R, Cox, GF, Dave, U, DeBaere, E, Field, M, Graham, JM, Gripp, KW, Greenstein, R, Gupta, N, Heidenreich, R, Hoffman, J, Hopkin, RJ, Jones, KL, Jones, MC, Kariminejad, A, Kogan, J, Lace, B, Leroy, J, Lynch, SA, McDonald, M, Meagher, K, Mendelsohn, N, Micule, I, Moeschler, J, Nampoothiri, S, Ohashi, K, Powell, CM, Ramanathan, S, Raskin, S, Roeder, E, Rio, M, Rope, AF, Sangha, K, Scheuerle, AE, Schneider, A, Shalev, S, Siu, V, Smith, R, Stevens, C, Tkemaladze, T, Toimie, J, Toriello, H, Turner, A, Wheeler, PG, White, SM, Young, T, Loomes, KM, Pipan, M, Harrington, AT, Zackai, E, Rajagopalan, R, Conlin, L, Deardorff, MA, McEldrew, D, Pie, J, Ramos, F, Musio, A, Kline, AD, Izumi, K, Raible, SE, Krantz, ID, Kaur, M, Blair, J, Devkota, B, Fortunato, S, Clark, D, Lawrence, A, Kim, J, Do, W, Semeo, B, Katz, O, Mehta, D, Yamamoto, N, Schindler, E, Al Rawi, Z, Wallace, N, Wilde, JJ, McCallum, J, Liu, J, Xu, D, Jackson, M, Rentas, S, Tayoun, AA, Zhe, Z, Abdul-Rahman, O, Allen, B, Angula, MA, Anyane-Yeboa, K, Argente, J, Arn, PH, Armstrong, L, Basel-Salmon, L, Baynam, G, Bird, LM, Bruegger, D, Ch'ng, G-S, Chitayat, D, Clark, R, Cox, GF, Dave, U, DeBaere, E, Field, M, Graham, JM, Gripp, KW, Greenstein, R, Gupta, N, Heidenreich, R, Hoffman, J, Hopkin, RJ, Jones, KL, Jones, MC, Kariminejad, A, Kogan, J, Lace, B, Leroy, J, Lynch, SA, McDonald, M, Meagher, K, Mendelsohn, N, Micule, I, Moeschler, J, Nampoothiri, S, Ohashi, K, Powell, CM, Ramanathan, S, Raskin, S, Roeder, E, Rio, M, Rope, AF, Sangha, K, Scheuerle, AE, Schneider, A, Shalev, S, Siu, V, Smith, R, Stevens, C, Tkemaladze, T, Toimie, J, Toriello, H, Turner, A, Wheeler, PG, White, SM, Young, T, Loomes, KM, Pipan, M, Harrington, AT, Zackai, E, Rajagopalan, R, Conlin, L, Deardorff, MA, McEldrew, D, Pie, J, Ramos, F, Musio, A, Kline, AD, Izumi, K, Raible, SE, and Krantz, ID

Abstract

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Published
2023

2. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Author

Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, Sadikovic, B, Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, and Sadikovic, B

Abstract

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Published
2022

3. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Author

Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Ostergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, Sadikovic, B, Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Ostergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, and Sadikovic, B

Abstract

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Published
2022

4. Cornelia de Lange syndrome in diverse populations.

Author

Dowsett, L, Porras, AR, Kruszka, P, Davis, B, Hu, T, Honey, E, Badoe, E, Thong, M-K, Leon, E, Girisha, KM, Shukla, A, Nayak, SS, Shotelersuk, V, Megarbane, A, Phadke, S, Sirisena, ND, Dissanayake, VHW, Ferreira, CR, Kisling, MS, Tanpaiboon, P, Uwineza, A, Mutesa, L, Tekendo-Ngongang, C, Wonkam, A, Fieggen, K, Batista, LC, Moretti-Ferreira, D, Stevenson, RE, Prijoles, EJ, Everman, D, Clarkson, K, Worthington, J, Kimonis, V, Hisama, F, Crowe, C, Wong, P, Johnson, K, Clark, RD, Bird, L, Masser-Frye, D, McDonald, M, Willems, P, Roeder, E, Saitta, S, Anyane-Yeoba, K, Demmer, L, Hamajima, N, Stark, Z, Gillies, G, Hudgins, L, Dave, U, Shalev, S, Siu, V, Ades, A, Dubbs, H, Raible, S, Kaur, M, Salzano, E, Jackson, L, Deardorff, M, Kline, A, Summar, M, Muenke, M, Linguraru, MG, Krantz, ID, Dowsett, L, Porras, AR, Kruszka, P, Davis, B, Hu, T, Honey, E, Badoe, E, Thong, M-K, Leon, E, Girisha, KM, Shukla, A, Nayak, SS, Shotelersuk, V, Megarbane, A, Phadke, S, Sirisena, ND, Dissanayake, VHW, Ferreira, CR, Kisling, MS, Tanpaiboon, P, Uwineza, A, Mutesa, L, Tekendo-Ngongang, C, Wonkam, A, Fieggen, K, Batista, LC, Moretti-Ferreira, D, Stevenson, RE, Prijoles, EJ, Everman, D, Clarkson, K, Worthington, J, Kimonis, V, Hisama, F, Crowe, C, Wong, P, Johnson, K, Clark, RD, Bird, L, Masser-Frye, D, McDonald, M, Willems, P, Roeder, E, Saitta, S, Anyane-Yeoba, K, Demmer, L, Hamajima, N, Stark, Z, Gillies, G, Hudgins, L, Dave, U, Shalev, S, Siu, V, Ades, A, Dubbs, H, Raible, S, Kaur, M, Salzano, E, Jackson, L, Deardorff, M, Kline, A, Summar, M, Muenke, M, Linguraru, MG, and Krantz, ID

Abstract

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Published
2019

5. Genetic characterization of two autosomal recessive disorders, Majewski-like and cerebral atrophy syndromes

Author

Lahiry, P, Robinson, J F, Siu, V, Puffenberger, E G, Strauss, K A, Hegele, R A, Rupar, C A, Lahiry, P, Robinson, J F, Siu, V, Puffenberger, E G, Strauss, K A, Hegele, R A, and Rupar, C A

Abstract

Introduction: We recently identified two lethal recessive disorders segregating within the same Old Order Amish pedigree. The first disorder, Majewski-like syndrome (MLS), has features that overlap with both Majewski short rib-polydactyly syndrome and hydrolethalus syndrome. MLS is a lethal multi-system disorder that affects the development of the brain, adrenal glands, pituitary gland and bone. The second disorder, cerebral atrophy syndrome (CAS), is characterized by progressive and global loss of brain tissue. Affected children present early in life with microcephaly, seizures, and psychomotor retardation, and possess distinctive MRI findings. The objective of this study was to identify the genetic bases of these disorders to provide prompt and reliable diagnosis for families. Methods: Assuming recessive inheritance and mutation homogeneity (autozygosity), we used Affymetrix 10,000-single nucleotide polymorphism (10K-SNP) to genotype all affected individuals and identify candidate regions. SNP data were analyzed using Agilent GT autozygosity mapping software. LOD scores were used to identify candidate regions, and genes within these regions were prioritized for sequencing. Results and Conclusion: Because the Ontario Anabaptist population is relatively small, genetically isolated, and historically young, we were able to robustly map candidate regions using relatively low marker density and only a few affected individuals. Our preliminary data is consistent with the clinical observation that MLS and CAS segregate independently, as recessive conditions, within the pedigree. Thus far, we have sequenced 12 genes within the MLS locus, all of which were normal. For CAS, autozygosity mapping yielded two loci with comparable linkage scores, one of which contained no observable mutations. Once the causative mutations have been identified for MLS and CAS, we intend to study their population frequencies and also to pursue in vitro studies of gene and protein functions.

Published
2007

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