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Gregory M Cooper,
Bradley P Coe,
Santhosh Girirajan,
Jill A Rosenfeld,
Tiffany H Vu,
Carl Baker,
Charles Williams,
Heather Stalker,
Rizwan Hamid,
Vickie Hannig, [......],
Marybeth Hummel,
Nora Alexander,
Jerome Gorski,
Jennifer Kussmann,
Vandana Shashi,
Krys Johnson,
Catherine Rehder,
Blake C Ballif,
Lisa G Shaffer,
Evan E Eichler
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ABSTRACT: To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.
Nature Genetics 08/2011; 43(9):838-46. · 35.53 Impact Factor
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Jill A Rosenfeld,
Kathleen Leppig,
Blake C Ballif, Heidi Thiese,
Christine Erdie-Lalena,
Erwati Bawle,
Sujatha Sastry,
J Edward Spence,
Anne Bandholz,
Urvashi Surti,
Jonathan Zonana,
Kory Keller,
Wendy Meschino,
Bassem A Bejjani,
Beth S Torchia,
Lisa G Shaffer
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ABSTRACT: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type.
We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4.
We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures.
On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.
Genetics in medicine: official journal of the American College of Medical Genetics 11/2009; 11(11):797-805. · 3.92 Impact Factor
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Ludwine Messiaen,
Suxia Yao,
Hilde Brems,
Tom Callens,
Achara Sathienkijkanchai,
Ellen Denayer,
Emily Spencer,
Pamela Arn,
Dusica Babovic-Vuksanovic,
Carolyn Bay, [......], Heidi Thiese,
Elaine H Zackai,
Raymon Vijzelaar,
Koji Taniguchi,
Toranoshin Ayada,
Fuyuki Okamoto,
Akihiko Yoshimura,
Annabel Parret,
Bruce Korf,
Eric Legius
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ABSTRACT: Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation.
To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients.
In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis.
Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations.
Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS.
A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.
JAMA The Journal of the American Medical Association 11/2009; 302(19):2111-8. · 30.03 Impact Factor
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Ludwine Messiaen,
Suxia Yao,
Hilde Brems,
Tom Callens,
Achara Sathienkijkanchai,
Ellen Denayer,
Emily Spencer,
Pamela Arn,
Dusica Babovic-Vuksanovic,
Carolyn Bay, [......], Heidi Thiese,
Elaine H. Zackai,
Raymon Vijzelaar,
Koji Taniguchi,
Toranoshin Ayada,
Fuyuki Okamoto,
Akihiko Yoshimura,
Annabel Parret,
Bruce Korf,
Eric Legius
[show abstract]
[hide abstract]
ABSTRACT: Context
Autosomal dominant inactivating sprouty-related EVH1 domain–containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation.Objective
To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1–like syndrome (NFLS) in a large cohort of patients.Design, Setting, and Participants
In a cross-sectional study, 22 unrelated probands carrying a SPRED1 loss-of-function (LOF) mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis.Main Outcome Measures
Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations.Results
Among 40 SPRED1 LOF-positive individuals from the clinical cohort, 20 (50%; 95% confidence interval [CI], 34%-66%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 40 SPRED1 LOF-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 26 pathogenic mutations in 33 probands and 8 probable nonpathogenic missense or silent mutations in 10 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS.Conclusions
A high SPRED1 mutation detection rate was found in NF1 mutation–negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.
Figures in this Article
Neurofibromatosis type 1 (NF1) (Online Mendelian Inheritance in Man [OMIM] 162200), an autosomal dominant disorder affecting approximately 1 in 3000 individuals worldwide,1- 2 results from inactivating mutations in the NF1 tumor suppressor encoding neurofibromin. Neurofibromatosis type 1 is characterized by multiple café au lait macules (CALMs), skin-fold freckling, iris Lisch nodules, and tumors of the nervous system such as optic pathway gliomas, astrocytomas, neurofibromas, and malignant peripheral nerve sheath tumors. Other frequently observed features are specific bone abnormalities, short stature, macrocephaly, and learning problems.
The NF1 diagnostic criteria were established at the National Institutes of Health (NIH) NF consensus conference in 1988,3 were updated in 1997,4 and are widely used to make the diagnosis using information obtained from physical examination, family history, and radiologic studies.
Neurofibromin is a negative regulator of RAS and pathogenic NF1 (NM_000267.2) mutations result in increased active RAS (guanosine triphosphate–bound RAS) and increased signaling through the downstream effectors such as the mitogen-activated protein kinase (MAPK) pathway.5 Recently, a genetically distinct but phenotypically similar disorder caused by heterozygous SPRED1 (NM_152594.2) mutations was identified (OMIM 611431).6- 8 Sprouty-related EVH1 domain–containing protein 1 (SPRED1), a member of the SPROUTY/SPRED family, negatively regulates MAPK signaling by inhibition of RAS-RAF interaction.9- 11 Inactivating SPRED1 mutations, resulting in increased MAPK signaling, were found in individuals from 5 families with multiple CALMs, freckling, and macrocephaly, with many fulfilling the NIH criteria for NF1 based on the presence of CALMs, freckling, or presence of a positive family history.6
In the original study,6 families suitably sized for linkage analysis had specifically been collected based on individuals with multiple CALMs with or without freckling and absence of a detectable NF1 mutation, which may imply that the observed phenotype and possible complications associated with the disorder might have been biased or underestimated. Similarly, the study by Spurlock et al8 and Pasmant et al7 primarily focused on SPRED1 analysis in patients with the mild pigmentary phenotype. Given the absence of neurofibromas in any patient described so far,6- 8 it has been proposed to refer to this new syndrome as Legius syndrome (as named in OMIM 611431)7- 8 and discontinue referring to it as neurofibromatosis type 1–like syndrome (NFLS).
In this study, we determined the phenotype in 22 unrelated probands and 18 relatives carrying a SPRED1 loss-of-function (LOF) mutation identified through clinical genetic testing. In addition, we carried out a cross-sectional study in an anonymous cohort of 1318 unrelated patients referred for NF1 genetic testing, in whom no NF1 mutation was found, allowing delineation of the SPRED1 mutational spectrum and estimation of the frequency of NFLS.
JAMA The Journal of the American Medical Association 302(19):2111-2118. · 30.03 Impact Factor
