Amanda Collins - Academia.edu (original) (raw)

Papers by Amanda Collins

Research paper thumbnail of CNTNAP2 and NRXN1 Are Mutated in Autosomal-Recessive Pitt-Hopkins-like Mental Retardation and Determine the Level of a Common Synaptic Protein in Drosophila

The American Journal of Human Genetics, 2009

Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of... more Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-I, the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-I and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2.

Research paper thumbnail of The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth

European Journal of Human Genetics, 2011

Research paper thumbnail of 3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome

We report the identification of six patients with 3q29 microdeletion syndrome. The clinical pheno... more We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features-including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation-were observed, but each feature was only found once, in a single patient. The microdeletion is ∼1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.

Research paper thumbnail of 3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome

The American Journal of Human Genetics, 2005

We report the identification of six patients with 3q29 microdeletion syndrome. The clinical pheno... more We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features-including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation-were observed, but each feature was only found once, in a single patient. The microdeletion is ∼1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.

Research paper thumbnail of Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Proceedings of the National Academy of Sciences, 2004

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extra... more Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1alpha of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a(+/-) mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a(+/-) mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a(+/-) mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

Research paper thumbnail of How genetically heterogeneous is Kabuki syndrome: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

European Journal of Human Genetics, 2012

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% pati... more MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Research paper thumbnail of CNTNAP2 and NRXN1 Are Mutated in Autosomal-Recessive Pitt-Hopkins-like Mental Retardation and Determine the Level of a Common Synaptic Protein in Drosophila

The American Journal of Human Genetics, 2009

Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of... more Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-I, the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-I and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2.

Research paper thumbnail of The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth

European Journal of Human Genetics, 2011

Research paper thumbnail of 3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome

We report the identification of six patients with 3q29 microdeletion syndrome. The clinical pheno... more We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features-including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation-were observed, but each feature was only found once, in a single patient. The microdeletion is ∼1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.

Research paper thumbnail of 3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome

The American Journal of Human Genetics, 2005

We report the identification of six patients with 3q29 microdeletion syndrome. The clinical pheno... more We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional features-including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation-were observed, but each feature was only found once, in a single patient. The microdeletion is ∼1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.

Research paper thumbnail of Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Proceedings of the National Academy of Sciences, 2004

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extra... more Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1alpha of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a(+/-) mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a(+/-) mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a(+/-) mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

Research paper thumbnail of How genetically heterogeneous is Kabuki syndrome: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

European Journal of Human Genetics, 2012

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% pati... more MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.