Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Pr... more Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Presently understood etiologies include both genetic and environmental factors, acting either alone, or more likely, in combination. The majority of patients without overt chromosomal abnormalities or recognizable associated syndromes have unidentified etiologies. A potential candidate gene, Twisted Gastrulation Homolog 1 (TWSG1), was previously suggested as a contributor to the complex genetics of human HPE based on (1) cytogenetic studies of patients with 18p deletions, (2) animal studies of TWSG1 deficient mice, and (3) the relationship of TWSG1 to bone morphogenetic protein (BMP) signaling, which modulates the primary pathway implicated in HPE, Sonic Hedgehog (SHH) signaling. Here we present the first analysis of a large cohort of patients with HPE for coding sequence variations in TWSG1. We also performed fine mapping of 18p for a subset of patients with partial 18p deletions. Surprisingly, minimal evidence for alterations of TWSG1 was found, suggesting that sequence alterations of TWSG1 are neither a common direct cause nor a frequent modifying factor for human HPE pathologies.
Glycogen storage disease type II (GSDII) is an autosomal recessive disorder resulting from inheri... more Glycogen storage disease type II (GSDII) is an autosomal recessive disorder resulting from inherited deficiency of the enzyme lysosomal acid alpha-glucosidase. Over 40 different mutations have been described but no large deletions have been previously identified. We now describe a homozygous large (9-kb) deletion extending from IVS 15 to 4 kb downstream of the terminal exon (exon 20), detected by polymerase chain reaction (PCR)-based methods. The deletion was initially suspected because of failure to amplify a contiguous group of exons by PCR. We hypothesized an Alu/Alu recombination, based on our prior demonstration by Southern blotting of Alu elements in the regions potentially flanking the deletion. Additional sequence analysis of genomic fragments confirmed the presence of Alu elements and allowed the design of flanking primers for PCR amplification. Amplification resulted in a smaller than normal fragment (0.7 vs. 10 kb) in homozygosity in the proband and in heterozygosity in her parents. Cloning and sequencing of the smaller than normal 0.7-kb deletion fragment revealed an Alu/Alu deletion junction. In heterozygosity this deletion would not be detected by currently standard PCR mutation detection methods. Based on other Alu-mediated deletions, this deletion is likely to be recurrent and should be screened for in all non-consanguineous GSDII patients, particularly when only one mutation has been identified and none of the 12 single-nucleotide polymorphisms in the deleted region are heterozygous. These observations also suggest that initial characterization of genes at disease-causing loci should include a search for Alu and other repetitive elements to facilitate subsequent PCR-based mutation analysis.
Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosi... more Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling. Published 2007 Wiley-Liss, Inc. {
Complex central nervous system (CNS) malformations frequently coexist with other developmental ab... more Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia À/À knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia þ/À and Nfia À/À phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia þ/À and Nfia À/À mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.
Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usua... more Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usually characterized by neonatal or intrauterine death, and, as such, only 26 cases have been reported. Physical manifestations such as antecubital and popliteal pterygia (webbing), syndactyly of fingers, toes and talipes are frequently reported. However, oral, facial, cranial and dental anomalies are often overlooked. This case focuses on the latter anomalies and the effect they have on the facial growth of a 5-year-old patient.
A sixteen-fold decreased incidence of fetal alcohol syndrome (ICM- 9-CM code 760.71) was reported... more A sixteen-fold decreased incidence of fetal alcohol syndrome (ICM- 9-CM code 760.71) was reported in the period 1985-1996 at the Albert Einstein College of Medicine affiliated hospitals. This result contrasts with the six-fold increased incidence in the period of 1979- 1993 reported by the Birth Defects Monitoring Program of the US Department of Health and Human Services. Factors which may
Several mutation sites have been found in the beta-galactosidase gene of patients with GM1 gangli... more Several mutation sites have been found in the beta-galactosidase gene of patients with GM1 gangliosidosis. In a previous report we found a common point mutation site in American patients with GM1 gangliosidosis resulting in a 208Arg --&amp;amp;gt; Cys amino acid substitution. From the patients&amp;amp;#39; family history, we suggested that this mutation may have come to South and North America via Puerto Rico. Four new patients with infantile GM1 gangliosidosis have been analyzed with allele-specific hybridization. Two siblings from Puerto Rico of Spanish ancestry are homozygous for this mutation. Another patient also from Puerto Rico is heterozygous for this allele, and another black patient does not have this mutation. These results support our initial hypothesis that this mutation has probably arisen in Puerto Rico.
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2005
ecause of advances in prenatal sonographic examinations, it is now possible to detect subtle faci... more ecause of advances in prenatal sonographic examinations, it is now possible to detect subtle facial dysmorphology in the second trimester. The detection of fetal craniofacial anomalies has resulted in the ability to prenatally diagnose genetic syndromes that might otherwise have gone undetected until birth. Marshall syndrome (MS) is a rare autosomal, dominantly inherited disorder that has a 50% recurrence risk in the offspring of an affected individual. First described by Marshall1 in 1958 in a multigenerational family with 7 affected individuals, the condition includes ophthalmologic abnormalities (hypertelorism, myopia, and cataracts), midface anomalies (flat or retruded nasal bridge, anteverted nares, and the appearance of large eyes with ocular hypertelorism), sensorineural hearing loss, and anhidrotic ectodermal dysplasia. Other frequent findings include short stature, cleft palate with or without Pierre Robin syndrome, spondyloepiphyseal abnormalities, and calcification of the falx cerebri. Since Marshall’s initial publication,1 only 8 additional families have been described in the English literature, illustrating the rarity of MS.2 Below we report the prenatal diagnosis of MS based on close assessment of the cranial features.
Ring chromosomes are estimated to occur in 3/10000 newborns and the simultaneous occurrence of tw... more Ring chromosomes are estimated to occur in 3/10000 newborns and the simultaneous occurrence of two autosomal rings must be a very rare event. Recently, the characterisation of these markers using fluorescence in situ hybridisation (FISH) has greatly enhanced cytogenetic-phenotypic correlations in patients with these marker chromosomes. This kind of analysis enabled us to clarify a unique karyotype containing a r(1) and a r(16) in identical twins born after a 26 week gestation with minimal somatic abnormalities. The origin of the rings was identified using a satellite and whole chromosome painting probes. FISH analysis showed the same abnormal female karyotype in both twins, 48,XX,+r(1)(p13q21),+r(16)(p11q11).ish r(1) (D1Z5+,wcpl+), r(16)(D16Z2+,wcp16+) in about two thirds of the cells. Each also had minor clones with a normal female karyotype or with one or the other supernumerary ring. Half of the r(1) contained CBG band negative material and the r(16) appeared to be totally CBG ba...
Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usua... more Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usually characterized by neonatal or intrauterine death, and, as such, only 26 cases have been reported. Physical manifestations such as antecubital and popliteal pterygia (webbing), syndactyly of fingers, toes and talipes are frequently reported. However, oral, facial, cranial and dental anomalies are often overlooked. This case focuses on the latter anomalies and the effect they have on the facial growth of a 5-year-old patient.
We attempted to measure the benefits of a community- wide hemoglobinopathy screening program by r... more We attempted to measure the benefits of a community- wide hemoglobinopathy screening program by review- ing the numbers of newborns detected to have a hemo- globinopathy, the level of utilization of prenatal diagnostic services, and the number of hemoglo- binopathies diagnosed prenatally. We measured the effect of our program on 14,051 infants born over a five year period and their families. Results: The incidence of the three common hemoglobinopathies was not altered over this five year period. Only 13% of at-risk couples received prenatal diagnosis, and only 8% of affected infants were diagnosed prenatally. We conclude that our program provided at-risk women with the diagnosis of affected fetuses and the option of possible termina- tion of pregnancy, both of which can be quantified. In addition, our program educated, counseled, and screened large numbers of individuals for hemoglo- binopathies resulting in a more educated and informed community.
Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Pr... more Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Presently understood etiologies include both genetic and environmental factors, acting either alone, or more likely, in combination. The majority of patients without overt chromosomal abnormalities or recognizable associated syndromes have unidentified etiologies. A potential candidate gene, Twisted Gastrulation Homolog 1 (TWSG1), was previously suggested as a contributor to the complex genetics of human HPE based on (1) cytogenetic studies of patients with 18p deletions, (2) animal studies of TWSG1 deficient mice, and (3) the relationship of TWSG1 to bone morphogenetic protein (BMP) signaling, which modulates the primary pathway implicated in HPE, Sonic Hedgehog (SHH) signaling. Here we present the first analysis of a large cohort of patients with HPE for coding sequence variations in TWSG1. We also performed fine mapping of 18p for a subset of patients with partial 18p deletions. Surprisingly, minimal evidence for alterations of TWSG1 was found, suggesting that sequence alterations of TWSG1 are neither a common direct cause nor a frequent modifying factor for human HPE pathologies.
Glycogen storage disease type II (GSDII) is an autosomal recessive disorder resulting from inheri... more Glycogen storage disease type II (GSDII) is an autosomal recessive disorder resulting from inherited deficiency of the enzyme lysosomal acid alpha-glucosidase. Over 40 different mutations have been described but no large deletions have been previously identified. We now describe a homozygous large (9-kb) deletion extending from IVS 15 to 4 kb downstream of the terminal exon (exon 20), detected by polymerase chain reaction (PCR)-based methods. The deletion was initially suspected because of failure to amplify a contiguous group of exons by PCR. We hypothesized an Alu/Alu recombination, based on our prior demonstration by Southern blotting of Alu elements in the regions potentially flanking the deletion. Additional sequence analysis of genomic fragments confirmed the presence of Alu elements and allowed the design of flanking primers for PCR amplification. Amplification resulted in a smaller than normal fragment (0.7 vs. 10 kb) in homozygosity in the proband and in heterozygosity in her parents. Cloning and sequencing of the smaller than normal 0.7-kb deletion fragment revealed an Alu/Alu deletion junction. In heterozygosity this deletion would not be detected by currently standard PCR mutation detection methods. Based on other Alu-mediated deletions, this deletion is likely to be recurrent and should be screened for in all non-consanguineous GSDII patients, particularly when only one mutation has been identified and none of the 12 single-nucleotide polymorphisms in the deleted region are heterozygous. These observations also suggest that initial characterization of genes at disease-causing loci should include a search for Alu and other repetitive elements to facilitate subsequent PCR-based mutation analysis.
Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosi... more Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling. Published 2007 Wiley-Liss, Inc. {
Complex central nervous system (CNS) malformations frequently coexist with other developmental ab... more Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia À/À knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia þ/À and Nfia À/À phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia þ/À and Nfia À/À mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.
Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usua... more Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usually characterized by neonatal or intrauterine death, and, as such, only 26 cases have been reported. Physical manifestations such as antecubital and popliteal pterygia (webbing), syndactyly of fingers, toes and talipes are frequently reported. However, oral, facial, cranial and dental anomalies are often overlooked. This case focuses on the latter anomalies and the effect they have on the facial growth of a 5-year-old patient.
A sixteen-fold decreased incidence of fetal alcohol syndrome (ICM- 9-CM code 760.71) was reported... more A sixteen-fold decreased incidence of fetal alcohol syndrome (ICM- 9-CM code 760.71) was reported in the period 1985-1996 at the Albert Einstein College of Medicine affiliated hospitals. This result contrasts with the six-fold increased incidence in the period of 1979- 1993 reported by the Birth Defects Monitoring Program of the US Department of Health and Human Services. Factors which may
Several mutation sites have been found in the beta-galactosidase gene of patients with GM1 gangli... more Several mutation sites have been found in the beta-galactosidase gene of patients with GM1 gangliosidosis. In a previous report we found a common point mutation site in American patients with GM1 gangliosidosis resulting in a 208Arg --&amp;amp;gt; Cys amino acid substitution. From the patients&amp;amp;#39; family history, we suggested that this mutation may have come to South and North America via Puerto Rico. Four new patients with infantile GM1 gangliosidosis have been analyzed with allele-specific hybridization. Two siblings from Puerto Rico of Spanish ancestry are homozygous for this mutation. Another patient also from Puerto Rico is heterozygous for this allele, and another black patient does not have this mutation. These results support our initial hypothesis that this mutation has probably arisen in Puerto Rico.
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2005
ecause of advances in prenatal sonographic examinations, it is now possible to detect subtle faci... more ecause of advances in prenatal sonographic examinations, it is now possible to detect subtle facial dysmorphology in the second trimester. The detection of fetal craniofacial anomalies has resulted in the ability to prenatally diagnose genetic syndromes that might otherwise have gone undetected until birth. Marshall syndrome (MS) is a rare autosomal, dominantly inherited disorder that has a 50% recurrence risk in the offspring of an affected individual. First described by Marshall1 in 1958 in a multigenerational family with 7 affected individuals, the condition includes ophthalmologic abnormalities (hypertelorism, myopia, and cataracts), midface anomalies (flat or retruded nasal bridge, anteverted nares, and the appearance of large eyes with ocular hypertelorism), sensorineural hearing loss, and anhidrotic ectodermal dysplasia. Other frequent findings include short stature, cleft palate with or without Pierre Robin syndrome, spondyloepiphyseal abnormalities, and calcification of the falx cerebri. Since Marshall’s initial publication,1 only 8 additional families have been described in the English literature, illustrating the rarity of MS.2 Below we report the prenatal diagnosis of MS based on close assessment of the cranial features.
Ring chromosomes are estimated to occur in 3/10000 newborns and the simultaneous occurrence of tw... more Ring chromosomes are estimated to occur in 3/10000 newborns and the simultaneous occurrence of two autosomal rings must be a very rare event. Recently, the characterisation of these markers using fluorescence in situ hybridisation (FISH) has greatly enhanced cytogenetic-phenotypic correlations in patients with these marker chromosomes. This kind of analysis enabled us to clarify a unique karyotype containing a r(1) and a r(16) in identical twins born after a 26 week gestation with minimal somatic abnormalities. The origin of the rings was identified using a satellite and whole chromosome painting probes. FISH analysis showed the same abnormal female karyotype in both twins, 48,XX,+r(1)(p13q21),+r(16)(p11q11).ish r(1) (D1Z5+,wcpl+), r(16)(D16Z2+,wcp16+) in about two thirds of the cells. Each also had minor clones with a normal female karyotype or with one or the other supernumerary ring. Half of the r(1) contained CBG band negative material and the r(16) appeared to be totally CBG ba...
Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usua... more Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usually characterized by neonatal or intrauterine death, and, as such, only 26 cases have been reported. Physical manifestations such as antecubital and popliteal pterygia (webbing), syndactyly of fingers, toes and talipes are frequently reported. However, oral, facial, cranial and dental anomalies are often overlooked. This case focuses on the latter anomalies and the effect they have on the facial growth of a 5-year-old patient.
We attempted to measure the benefits of a community- wide hemoglobinopathy screening program by r... more We attempted to measure the benefits of a community- wide hemoglobinopathy screening program by review- ing the numbers of newborns detected to have a hemo- globinopathy, the level of utilization of prenatal diagnostic services, and the number of hemoglo- binopathies diagnosed prenatally. We measured the effect of our program on 14,051 infants born over a five year period and their families. Results: The incidence of the three common hemoglobinopathies was not altered over this five year period. Only 13% of at-risk couples received prenatal diagnosis, and only 8% of affected infants were diagnosed prenatally. We conclude that our program provided at-risk women with the diagnosis of affected fetuses and the option of possible termina- tion of pregnancy, both of which can be quantified. In addition, our program educated, counseled, and screened large numbers of individuals for hemoglo- binopathies resulting in a more educated and informed community.
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Papers by Alan Shanske