Background Conduct a comprehensive survey of FASD knowledge, skill, and attitudes regarding recog... more Background Conduct a comprehensive survey of FASD knowledge, skill, and attitudes regarding recognition, diagnosis, treatment, and prevention among family physicians in the Midwest. Methods A 35 question survey on FASD recognition, diagnosis, treatment, and prevention was sent to a random sample of 1,000 active members of the AAFP from Missouri and the 5 surrounding states. Results Twelve percent of participants returned surveys. The mean age was 44 years, 64 % were male, 86.3% were Caucasian, and 43.6 % were from rural areas. The survey revealed that the great majority of family physicians possess general knowledge about FAS and the effects of alcohol on children, including the importance of early diagnosis and reducing secondary disabilities. However, the survey revealed significant deficits when it came to recognition and diagnosis of FAS, with the great majority of family physicians uncertain about the facial dysmorphology features associated with FAS. In addition, the majority ...
Do you have adequate knowledge of the hallmarks of fetal alcohol syndrome and fetal alcohol spect... more Do you have adequate knowledge of the hallmarks of fetal alcohol syndrome and fetal alcohol spectrum disorders? Can you identify pregnant women who are at risk for having a child with the disorder? A large random sample survey of American Psychological Association members uncovered large deficits in psychologists ’ knowledge about the diagnosis, treatment, and prevention of these problems. The authors report accurate information about these damaging disorders and identify the errors most commonly demonstrated by those surveyed.
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Fetal Alcohol Syndrome (FAS) occurs in approximately 3 of 1,000 live births in the general popula... more Fetal Alcohol Syndrome (FAS) occurs in approximately 3 of 1,000 live births in the general population of the U.S. and is the leading known cause of mental retardation. The Midwest Regional Fetal Alcohol Syndrome Training Center (MRFASTC) surveyed 1,000 licensed occupational therapists (OT) of the American Occupational Therapists Association in a six-state Midwest region, including Missouri, Iowa, Nebraska, Kansas, Oklahoma, and Arkansas to assess knowledge and attitudes regarding FAS. Nearly 20% of the OTs responded. Of the respondents, nearly 94% regarded at least 1 drink per day as being 'heavy' in a pregnant woman. There was an increase in the number of respondents who thought it was acceptable to consume 1 drink or more with each advancing trimester of pregnancy. 92% of the OTs indicated a willingness to counsel a mother of a child having FAS, but 96% indicated a poor to fair ability to select valid and reliable assessment instruments for screening a child for FAS. Only ...
L1syndrome is an X‐linked disorder manifesting with congenital hydrocephalus, adducted thumbs and... more L1syndrome is an X‐linked disorder manifesting with congenital hydrocephalus, adducted thumbs and spasticity. There are rare cases of L1 syndrome and coincident Hirschsprung disease, with mutations in the L1CAM gene thought to underlie both. We present a novel pathogenic L1CAM variant in someone with L1 syndrome and Hirschsprung disease.
Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019,... more Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcript... more The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2‐related overgrowth) and Cohen‐Gibson syndrome (EED‐related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver‐like phenotype with a rare coding SUZ12 variant—the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver‐like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre‐ and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly‐affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically‐recognizable syndromes emerge from different variant subtypes.
Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, l... more Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization.
American journal of medical genetics. Part A, Apr 1, 2018
Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated wit... more Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.
To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first... more To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p.A143T variant); Pompe disease, n = 10 (1 in 21 979); Gaucher disease, n = 5 (1 in 43 959); mucopolysaccharidosis (MPS) type 1, n = 1 (1 in 219 793); and Niemann-Pick disease type A/B, n = 2 (1 in 109 897). Twenty-two infants had a positive screen for 1 of the 5 disorders but could not be classified as either affected or unaffected after follow-up testing, including genotyping. Pseudodeficiencies for alpha-L-iduronidase and alpha-glucosidase were de...
Bicuspid aortic valve (BAV) is considered an autosomal dominant condition, which is commonly asso... more Bicuspid aortic valve (BAV) is considered an autosomal dominant condition, which is commonly associated with thoracic aortic aneurysm. Both conditions pose the risk of valvular and aortic complications not only for affected patients but also for genetically related persons as well. The genetic underpinnings of these disease processes, which are in various stages of elucidation, have implications for screening and risk prognostication. To analyze genetic differences between 2 pairs of monozygotic twins that had discordant aortic valve morphology, with 1 twin in each pair having a BAV and the other having a trileaflet aortic valve. Two pairs of twins that were objectively determined to be monozygotic were examined at a tertiary care medical center associated with an academic medical center. Aortic valves that were surgically excised for clinical indications were examined for morphology. Whole-exome sequencing was performed for the twin pair that had discordance of aortic valve and aor...
American journal of medical genetics. Part A, Oct 23, 2016
In 1994, Braddock and Carey first reported two unrelated girls with a new multiple malformation s... more In 1994, Braddock and Carey first reported two unrelated girls with a new multiple malformation syndrome. The primary features included Pierre Robin sequence, persistent neonatal-onset thrombocytopenia, agenesis of the corpus callosum, a distinctive facies, enamel hypoplasia, and severe developmental delay. Since that time, there have been multiple other reported patients with a similar phenotype. In addition, several reports of thrombocytopenia and developmental delay have been documented in association with deletions in the Down syndrome critical region at 21q22. The similarity of the reported cases with deletions involving 21q22 with the clinical presentation of the two patients with Braddock-Carey syndrome resulted in a reinvestigation of the genetic etiology of these two patients 20 years after the original study. This investigation provides evidence that the etiology of this and other "Fanconi-like" disorders represent a newly recognized contiguous gene deletion synd...
Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 da... more Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 days of age. Continuous venovenous hemodialysis was performed successfully for both infants via extracorporeal membrane oxygenation pump, and both rapidly improved. They were taken off continuous venovenous hemodialysis and extracorporeal membrane oxygenation and discharged with dietary therapy. At 3 years of age, neurodevelopment showed globally delayed milestones.
Prader-Willi (PWS) and Angelman (AS) syndromes are genetic disorders with multiple well-known mec... more Prader-Willi (PWS) and Angelman (AS) syndromes are genetic disorders with multiple well-known mechanisms. Approximately 70% of individuals with PWS or AS have a ~4 Mb deletion of 15q11-q13, while the remainder have UPD15, an imprinting defect or, in the case of UBE3A, a sequence variant. Rarely have focal deletions been reported. We report here on three such unusual cases from our clinical microarray experience. Case 1 was a 2-1/2 year old boy with global developmental delay, short stature, microcephaly, failure to thrive and possible hearing loss. This boy, his healthy mother and maternal grandfather had a 36 kb deletion involving only noncoding exons 1 and 2 of UBE3A (NM_130839). Although previously unreported, this deletion is considered likely pathogenic based upon the AS phenotype in the proband and the inheritance pattern in this family. Case 2 was a 2-1/2 year old girl with epilepsy referred for testing on our childhood epilepsy panel which includes sequencing and copy number analysis of 58 relevant genes. Exon-level array showed an intragenic deletion of exons 2–4 of UBE3A. Methylation -specific MLPA (MS-MLPA) showed normal imprinting. Parental testing may be informative in assisting diagnosis since only maternal inheritance would be consistent with AS. Case 3 was the phenotypically normal father of a boy with PWS and a known SNRPN deletion. Array showed that the father had a 109 kb deletion of exons 4–12 of SNRPN (NM_022808) as well as the upstream reading frame (SNURF). MS-MLPA showed that this deletion was on the maternally derived chromosome. Although rare, intragenic or gene deletion of either UBE3A or SNRPN rather than the common 4 Mb deletion can be observed with PWS and AS. An assay which provides exon level coverage of these genes is important when interrogating this region.
Background Conduct a comprehensive survey of FASD knowledge, skill, and attitudes regarding recog... more Background Conduct a comprehensive survey of FASD knowledge, skill, and attitudes regarding recognition, diagnosis, treatment, and prevention among family physicians in the Midwest. Methods A 35 question survey on FASD recognition, diagnosis, treatment, and prevention was sent to a random sample of 1,000 active members of the AAFP from Missouri and the 5 surrounding states. Results Twelve percent of participants returned surveys. The mean age was 44 years, 64 % were male, 86.3% were Caucasian, and 43.6 % were from rural areas. The survey revealed that the great majority of family physicians possess general knowledge about FAS and the effects of alcohol on children, including the importance of early diagnosis and reducing secondary disabilities. However, the survey revealed significant deficits when it came to recognition and diagnosis of FAS, with the great majority of family physicians uncertain about the facial dysmorphology features associated with FAS. In addition, the majority ...
Do you have adequate knowledge of the hallmarks of fetal alcohol syndrome and fetal alcohol spect... more Do you have adequate knowledge of the hallmarks of fetal alcohol syndrome and fetal alcohol spectrum disorders? Can you identify pregnant women who are at risk for having a child with the disorder? A large random sample survey of American Psychological Association members uncovered large deficits in psychologists ’ knowledge about the diagnosis, treatment, and prevention of these problems. The authors report accurate information about these damaging disorders and identify the errors most commonly demonstrated by those surveyed.
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Fetal Alcohol Syndrome (FAS) occurs in approximately 3 of 1,000 live births in the general popula... more Fetal Alcohol Syndrome (FAS) occurs in approximately 3 of 1,000 live births in the general population of the U.S. and is the leading known cause of mental retardation. The Midwest Regional Fetal Alcohol Syndrome Training Center (MRFASTC) surveyed 1,000 licensed occupational therapists (OT) of the American Occupational Therapists Association in a six-state Midwest region, including Missouri, Iowa, Nebraska, Kansas, Oklahoma, and Arkansas to assess knowledge and attitudes regarding FAS. Nearly 20% of the OTs responded. Of the respondents, nearly 94% regarded at least 1 drink per day as being 'heavy' in a pregnant woman. There was an increase in the number of respondents who thought it was acceptable to consume 1 drink or more with each advancing trimester of pregnancy. 92% of the OTs indicated a willingness to counsel a mother of a child having FAS, but 96% indicated a poor to fair ability to select valid and reliable assessment instruments for screening a child for FAS. Only ...
L1syndrome is an X‐linked disorder manifesting with congenital hydrocephalus, adducted thumbs and... more L1syndrome is an X‐linked disorder manifesting with congenital hydrocephalus, adducted thumbs and spasticity. There are rare cases of L1 syndrome and coincident Hirschsprung disease, with mutations in the L1CAM gene thought to underlie both. We present a novel pathogenic L1CAM variant in someone with L1 syndrome and Hirschsprung disease.
Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019,... more Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcript... more The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2‐related overgrowth) and Cohen‐Gibson syndrome (EED‐related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver‐like phenotype with a rare coding SUZ12 variant—the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver‐like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre‐ and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly‐affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically‐recognizable syndromes emerge from different variant subtypes.
Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, l... more Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation that does not result in cytoplasmic or nuclear aggregation of the protein but maintains normal nuclear localization.
American journal of medical genetics. Part A, Apr 1, 2018
Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated wit... more Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.
To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first... more To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p.A143T variant); Pompe disease, n = 10 (1 in 21 979); Gaucher disease, n = 5 (1 in 43 959); mucopolysaccharidosis (MPS) type 1, n = 1 (1 in 219 793); and Niemann-Pick disease type A/B, n = 2 (1 in 109 897). Twenty-two infants had a positive screen for 1 of the 5 disorders but could not be classified as either affected or unaffected after follow-up testing, including genotyping. Pseudodeficiencies for alpha-L-iduronidase and alpha-glucosidase were de...
Bicuspid aortic valve (BAV) is considered an autosomal dominant condition, which is commonly asso... more Bicuspid aortic valve (BAV) is considered an autosomal dominant condition, which is commonly associated with thoracic aortic aneurysm. Both conditions pose the risk of valvular and aortic complications not only for affected patients but also for genetically related persons as well. The genetic underpinnings of these disease processes, which are in various stages of elucidation, have implications for screening and risk prognostication. To analyze genetic differences between 2 pairs of monozygotic twins that had discordant aortic valve morphology, with 1 twin in each pair having a BAV and the other having a trileaflet aortic valve. Two pairs of twins that were objectively determined to be monozygotic were examined at a tertiary care medical center associated with an academic medical center. Aortic valves that were surgically excised for clinical indications were examined for morphology. Whole-exome sequencing was performed for the twin pair that had discordance of aortic valve and aor...
American journal of medical genetics. Part A, Oct 23, 2016
In 1994, Braddock and Carey first reported two unrelated girls with a new multiple malformation s... more In 1994, Braddock and Carey first reported two unrelated girls with a new multiple malformation syndrome. The primary features included Pierre Robin sequence, persistent neonatal-onset thrombocytopenia, agenesis of the corpus callosum, a distinctive facies, enamel hypoplasia, and severe developmental delay. Since that time, there have been multiple other reported patients with a similar phenotype. In addition, several reports of thrombocytopenia and developmental delay have been documented in association with deletions in the Down syndrome critical region at 21q22. The similarity of the reported cases with deletions involving 21q22 with the clinical presentation of the two patients with Braddock-Carey syndrome resulted in a reinvestigation of the genetic etiology of these two patients 20 years after the original study. This investigation provides evidence that the etiology of this and other "Fanconi-like" disorders represent a newly recognized contiguous gene deletion synd...
Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 da... more Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 days of age. Continuous venovenous hemodialysis was performed successfully for both infants via extracorporeal membrane oxygenation pump, and both rapidly improved. They were taken off continuous venovenous hemodialysis and extracorporeal membrane oxygenation and discharged with dietary therapy. At 3 years of age, neurodevelopment showed globally delayed milestones.
Prader-Willi (PWS) and Angelman (AS) syndromes are genetic disorders with multiple well-known mec... more Prader-Willi (PWS) and Angelman (AS) syndromes are genetic disorders with multiple well-known mechanisms. Approximately 70% of individuals with PWS or AS have a ~4 Mb deletion of 15q11-q13, while the remainder have UPD15, an imprinting defect or, in the case of UBE3A, a sequence variant. Rarely have focal deletions been reported. We report here on three such unusual cases from our clinical microarray experience. Case 1 was a 2-1/2 year old boy with global developmental delay, short stature, microcephaly, failure to thrive and possible hearing loss. This boy, his healthy mother and maternal grandfather had a 36 kb deletion involving only noncoding exons 1 and 2 of UBE3A (NM_130839). Although previously unreported, this deletion is considered likely pathogenic based upon the AS phenotype in the proband and the inheritance pattern in this family. Case 2 was a 2-1/2 year old girl with epilepsy referred for testing on our childhood epilepsy panel which includes sequencing and copy number analysis of 58 relevant genes. Exon-level array showed an intragenic deletion of exons 2–4 of UBE3A. Methylation -specific MLPA (MS-MLPA) showed normal imprinting. Parental testing may be informative in assisting diagnosis since only maternal inheritance would be consistent with AS. Case 3 was the phenotypically normal father of a boy with PWS and a known SNRPN deletion. Array showed that the father had a 109 kb deletion of exons 4–12 of SNRPN (NM_022808) as well as the upstream reading frame (SNURF). MS-MLPA showed that this deletion was on the maternally derived chromosome. Although rare, intragenic or gene deletion of either UBE3A or SNRPN rather than the common 4 Mb deletion can be observed with PWS and AS. An assay which provides exon level coverage of these genes is important when interrogating this region.
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Papers by Stephen Braddock