RESUMO
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.
RESUMO
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
Assuntos
Transtorno do Espectro Autista/genética , Deleção de Genes , Duplicação Gênica , Alelos , Sequência de Aminoácidos , Sequência de Bases , Estudos de Casos e Controles , Criança , Variações do Número de Cópias de DNA , Feminino , Frequência do Gene , Rearranjo Gênico , Loci Gênicos , Genoma Humano , Técnicas de Genotipagem , Humanos , Mutação INDEL , Masculino , Análise em Microsséries , Dados de Sequência Molecular , Linhagem , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.
Assuntos
Fatores de Transcrição Forkhead/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Transtorno do Espectro Autista/genética , Face/anormalidades , Feminino , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Transtornos da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras/genética , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Estabilidade Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Síndrome , Transcrição GênicaRESUMO
Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy.
Assuntos
Hérnia Hiatal/diagnóstico , Hérnia Hiatal/genética , Homozigoto , Microcefalia/diagnóstico , Microcefalia/genética , Mutação de Sentido Incorreto , Nefrose/diagnóstico , Nefrose/genética , Proteínas/genética , Estudos de Coortes , Exoma , Fácies , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Proteínas/químicaRESUMO
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that show impaired communication and socialization, restricted interests, and stereotypical behavioral patterns. Recent advances in molecular medicine and high throughput screenings, such as array comparative genomic hybridization (CGH) and exome and whole genome sequencing, have revealed both novel insights and new questions about the nature of this spectrum of disorders. What has emerged is a better understanding about the genetic architecture of various genetic subtypes of ASD and correlations of genetic mutations with specific autism subtypes. Based on this new information, we outline a strategy for advancing diagnosis, prognosis, and counseling for patients and families.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/psicologia , Deleção de Genes , Duplicação Gênica , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/genética , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Proteína 2 de Ligação a Metil-CpG/genética , Distrofia Muscular de Duchenne/complicações , Proteínas do Tecido Nervoso/genética , PTEN Fosfo-Hidrolase/genética , Índice de Gravidade de Doença , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaRESUMO
The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Criança , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial/genéticaRESUMO
OBJECTIVE: Determination of fetal sex is an important part of detailed second-trimester ultrasonography. This task can be hindered by the fetal position, a low amniotic fluid volume, and advanced gestational age. Identification of fetal sex is further important in multiple gestations and prior histories of indeterminate-sex pregnancies. The goal of the study was to compare the effectiveness of 2-dimensional ultrasonography (2DUS) versus 3-dimensional ultrasonography (3DUS) at sex identification and to determine how genitalia measurements taken with 3DUS technology compare with measurements taken with 2DUS. METHODS: A total of 111 patients at or beyond 16 weeks' gestation were recruited. Assignments of fetal sex using 2DUS and 3DUS were compared by the test of proportions. The actual neonatal sex was obtained after delivery. Given such small number of misdiagnoses by either 2DUS or 3DUS, the accuracies of the two modalities were not found to be statistically distinguishable from one another (P = .5585). The penile length, scrotal width, and bilabial diameter according to gestational age were measured and compared with previously published 2DUS data by t tests. RESULTS: Sexes were assigned and interpreted in 65 cases. Ranges of genitalia measurements were plotted against gestational age and were found to be comparable with published data. There was a dramatic difference between the bilabial diameter and scrotal width with advancing gestational age that made sex determination much easier in the third trimester. CONCLUSIONS: Although 3DUS did not have better prediction of fetal sex when compared with 2DUS, it may be a useful tool in conjunction with traditional imaging techniques in assigning fetal sex.
Assuntos
Gônadas/diagnóstico por imagem , Gônadas/embriologia , Aumento da Imagem/métodos , Imageamento Tridimensional/métodos , Análise para Determinação do Sexo/métodos , Ultrassonografia Pré-Natal/métodos , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.
Assuntos
Região Variável de Imunoglobulina/genética , Mutação , Proteínas Recombinantes/genética , Malformações Vasculares/genética , Malformações da Veia de Galeno/genética , Malformações Arteriovenosas , Família , Humanos , Fenótipo , Anticorpos de Cadeia Única , Síndrome , Proteína p120 Ativadora de GTPaseRESUMO
BACKGROUND: The acardiac human fetus represents an accident of monozygotic twinning or higher multiple births due to an artery-to-artery and a vein-to-vein anastomosis in the monochorial placenta. Blood returning to the placenta through the umbilical artery of a normal cotwin is directed into the umbilical artery of the acardiac twin such that blood reaching the cranial end of the embryo is likely to be poorly oxygenated resulting in a number of structural defects including oral clefts. Although retrograde perfusion as a cause of hypoxia is unique to the acardiac fetus, there is ample evidence from animal studies that hypoxia is associated with facial clefting. METHODS: Twenty-six acardiac fetuses were examined at UCSD Medical Center between 1974 and 2003. RESULTS: In 12 of the 26, the cephalic end of the fetus was sufficiently intact to document the structures of the face. Of these, cleft lip +/- palate was present in five and cleft palate alone was present in one. In all six, the oral cleft followed the normal planes of facial closure. The cotwin in all six cases was normal. CONCLUSIONS: This article suggests that decreased blood flow/hypoxia to the cephalic end of the fetus may be an important contributor to the development of cleft lip +/- palate and cleft palate alone in the acardiac fetus and raises the possibility that this may also be a mechanism responsible for oral clefting in singletons.
Assuntos
Anormalidades Múltiplas/patologia , Fenda Labial/etiologia , Fissura Palatina/etiologia , Coração Fetal/anormalidades , Feto/anormalidades , Hipóxia/complicações , Anormalidades Teratoides Graves/patologia , Fenda Labial/complicações , Fenda Labial/patologia , Fissura Palatina/complicações , Fissura Palatina/patologia , Feminino , Morte Fetal/patologia , Feto/irrigação sanguínea , Feto/patologia , Humanos , Circulação Placentária/fisiologia , GravidezRESUMO
The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.
Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Variação Genética , Herança Paterna , Regiões Promotoras Genéticas/genética , Éxons , Regulação da Expressão Gênica , Genoma Humano , Humanos , Mutação , Linhagem , RNA não Traduzido/genética , Seleção Genética , Deleção de Sequência , Fatores de Transcrição/genéticaRESUMO
Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.
Assuntos
Encéfalo/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Microcefalia/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Consanguinidade , Feminino , Genes Letais , Estudos de Associação Genética , Células HEK293 , Humanos , Lactente , Masculino , Camundongos Knockout , Mutação de Sentido Incorreto , Simportadores , Síndrome , Peixe-ZebraRESUMO
Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.
Assuntos
Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Predisposição Genética para Doença , Proteínas Mutantes/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades do Olho/genética , Frequência do Gene , Testes Genéticos , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Doenças Renais Císticas/genética , RNA Interferente Pequeno/genéticaRESUMO
Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.
Assuntos
Doenças Cerebelares/genética , Cerebelo/patologia , Lisossomos/metabolismo , Fagossomos/metabolismo , Nexinas de Classificação/genética , Ataxias Espinocerebelares/genética , Animais , Atrofia/genética , Autofagia , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Lactente , Escore Lod , Doenças por Armazenamento dos Lisossomos/genética , Masculino , Mutação , Síndrome , Peixe-ZebraRESUMO
OBJECTIVES: To describe our experience using propofol sedation to facilitate elective diagnostic and therapeutic procedures, and to document the safety profile of propofol in this setting. DESIGN: Retrospective consecutive case series and review of the literature. SETTING: Pediatric intensive care unit of a United States Navy tertiary care medical center. PATIENTS: Children receiving propofol for procedural sedation over an 18-month period. OUTCOME MEASURES: Descriptive features of sedation including adverse events. RESULTS: During the study period, 91 children received propofol to facilitate the performance of 110 medical procedures. The mean induction dose was 2.41 mg/kg, the mean infusion rate was 179.3 microg/kg/min, and the mean total dose of propofol administered was 4.23 mg/kg. In all cases, sedation was successfully achieved. The average length of stay in the PICU was 108.4 minutes. Three children (3.3%) had transient episodes of oxygen desaturation that improved with repositioning of the airway. No child required placement of an endotracheal tube. Three (3.3%) children experienced hypotension requiring a decrease in the infusion rate of propofol and a 10-mL/kg bolus infusion of normal saline. No cardiac arrhythmias or adverse neurologic effects secondary to propofol infusion were identified. CONCLUSIONS: Pediatric intensivists can safely and effectively administer propofol to facilitate the performance of diagnostic and therapeutic procedures outside the operating room setting.
Assuntos
Hipnóticos e Sedativos/uso terapêutico , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Propofol/uso terapêutico , Criança , Diagnóstico , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipotensão/induzido quimicamente , Tempo de Internação/estatística & dados numéricos , Propofol/efeitos adversos , Estudos Retrospectivos , Segurança , TerapêuticaRESUMO
Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.
Assuntos
Exoma/genética , Estudos de Associação Genética , Doença dos Neurônios Motores/genética , Neurônios/metabolismo , Tratos Piramidais/metabolismo , Paraplegia Espástica Hereditária/genética , Animais , Axônios/fisiologia , Transporte Biológico/genética , Estudos de Coortes , Redes Reguladoras de Genes , Humanos , Mutação , Nucleotídeos/genética , Nucleotídeos/metabolismo , Análise de Sequência de DNA , Sinapses/fisiologia , Transcriptoma , Peixe-ZebraRESUMO
INTRODUCTION: Acne vulgaris is one of the most common skin conditions in children and adolescents. The presentation, differential diagnosis, and association of acne with systemic pathology differs by age of presentation. Current acknowledged guidelines for the diagnosis and management of pediatric acne are lacking, and there are variations in management across the spectrum of primary and specialty care. The American Acne and Rosacea Society convened a panel of pediatric dermatologists, pediatricians, and dermatologists with expertise in acne to develop recommendations for the management of pediatric acne and evidence-based treatment algorithms. METHODS: Ten major topic areas in the diagnosis and treatment of pediatric acne were identified. A thorough literature search was performed and articles identified, reviewed, and assessed for evidence grading. Each topic area was assigned to 2 expert reviewers who developed and presented summaries and recommendations for critique and editing. Furthermore, the Strength of Recommendation Taxonomy, including ratings for the strength of recommendation for a body of evidence, was used throughout for the consensus recommendations for the evaluation and management of pediatric acne. Practical evidence-based treatment algorithms also were developed. RESULTS: Recommendations were put forth regarding the classification, diagnosis, evaluation, and management of pediatric acne, based on age and pubertal status. Treatment considerations include the use of over-the-counter products, topical benzoyl peroxide, topical retinoids, topical antibiotics, oral antibiotics, hormonal therapy, and isotretinoin. Simplified treatment algorithms and recommendations are presented in detail for adolescent, preadolescent, infantile, and neonatal acne. Other considerations, including psychosocial effects of acne, adherence to treatment regimens, and the role of diet and acne, also are discussed. CONCLUSIONS: These expert recommendations by the American Acne and Rosacea Society as reviewed and endorsed by the American Academy of Pediatrics constitute the first detailed, evidence-based clinical guidelines for the management of pediatric acne including issues of special concern when treating pediatric patients.
Assuntos
Acne Vulgar/diagnóstico , Acne Vulgar/tratamento farmacológico , Antibacterianos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Acne Vulgar/classificação , Adolescente , Criança , Fármacos Dermatológicos/efeitos adversos , Diagnóstico Diferencial , Medicina Baseada em Evidências , Humanos , Lactente , Recém-Nascido , Retinoides/efeitos adversos , Retinoides/uso terapêutico , Índice de Gravidade de DoençaRESUMO
The mechanisms by which maternal diabetes causes malformations in the offspring have yet to be elucidated. The purpose of this report is twofold: first, to describe three male infants born with multiple congenital anomalies and megalourethra, a defect which has not been previously reported in infants of women with diabetes; and second, to indicate that the defects seen in association with megalourethra in these three infants are similar to those seen as a consequence of abnormalities in sonic hedgehog, suggesting that maternal diabetes may affect sonic hedgehog expression in susceptible tissues during critical stages of development.