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1.  Pancreatic Insufficiency is Not a Prevalent Problem in Alagille Syndrome 
Alagille syndrome (ALGS) is an inherited multisystem disorder in which pancreatic insufficiency has been regarded a minor but important clinical manifestation. As part of a multi-center prospective study, 42 ALGS patients underwent fecal elastase (FE) measurement to screen for exocrine pancreatic insufficiency (PI). FE measurements were normal (>200 μg/g) in 40 (95%) and indeterminate (100-200 μg/g) in 2 (5%). Since FE is the most reliable screen for PI, these data suggest that PI is not a prevalent problem in ALGS.
PMCID: PMC3666161  PMID: 22614108
2.  NOTCH2 mutations in Alagille syndrome 
Journal of medical genetics  2011;49(2):138-144.
Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.
The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.
Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.
This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
PMCID: PMC3682659  PMID: 22209762
3.  Common variants at five new loci associated with early-onset inflammatory bowel disease 
Nature Genetics  2009;41(12):1335-1340.
The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD1. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn’s disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.
PMCID: PMC3267927  PMID: 19915574
4.  Pathologic Lower Extremity Fractures in Children with Alagille Syndrome 
In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, one of the leading inherited causes of pediatric cholestatic liver disease.
Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance or The Children’s Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to one question, and details characterizing each patient’s medical, growth, and fracture history were obtained through chart review and telephone contact.
Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures/10,000 person years (95% CI = 206.5, 698.0) and 127.6 femur fractures/10,000 person-years (95% CI = 42.4, 297.7). There were no differences in gender, age distribution or organ system involvement between the fracture and no-fracture groups.
Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. While this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and to explore factors contributing to bone fragility in these children.
PMCID: PMC2893241  PMID: 20453673
Alagille syndrome; fracture; osteomalacia
5.  Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects 
Human Molecular Genetics  2010;19(10):2059-2067.
Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies.
PMCID: PMC2860894  PMID: 20176734
6.  A Longitudinal Study to Identify Laboratory Predictors of Liver Disease Outcome in Alagille Syndrome 
Liver disease in Alagille syndrome is highly variable ranging from biochemical abnormalities only to end-stage disease. It is not possible to predict whether a child with cholestasis will have improvement or progression of liver disease. This poses a challenge to the clinician in terms of timing therapies. The study aim was to identify laboratory markers present under the age of 5 years that could predict the ultimate outcome of liver disease in Alagille syndrome.
A retrospective review of laboratory data from 33 Alagille syndrome subjects was performed. Patients greater than 10 years of age were stratified into mild (22) and severe (11) hepatic outcome groups. Non-parametric analysis was performed on longitudinal data from birth-5years to determine association with hepatic outcome. JAGGED1 mutational analysis was performed on available samples.
The following variables were statistically different between severe and mild outcome groups; total bilirubin (p= 0.0001), conjugated bilirubin (p =0.0066), and cholesterol (p =0.0022). Further analysis revealed cutoff values that differentiated between severe and mild outcomes; total bilirubin 6.5mg/dL(111micromol/L), conjugated bilirubin 4.5mg/dL(77micromol/L) and cholesterol 520mg/dL(13.5mmol/L). Genetic analysis of JAGGED1 mutations did not reveal genotype-phenotype correlation.
Total bilirubin above 6.5mg/dL, conjugated bilirubin above 4.5mg/dL and cholesterol above 520mg/dL under the age of 5 years are likely to be associated with severe liver disease in later life. These data represent cutoff values below which a child is likely to have a benign outcome and above which more aggressive therapy may be warranted, and can thus be used to guide management.
PMCID: PMC2861305  PMID: 20421762
Alagille; liver; cholestasis; transplantation
7.  SNP array mapping of 20p deletions: Genotypes, Phenotypes and Copy Number Variation 
Human mutation  2009;30(3):371-378.
The use of array technology to define chromosome deletions and duplications is bringing us closer to establishing a genotype/phenotype map of genomic copy number alterations. We studied 21 patients and 5 relatives with deletions of the short arm of chromosome 20 using the Illumina HumanHap550 SNP array to 1) more accurately determine the deletion sizes, 2) identify and compare breakpoints, 3) establish genotype/phenotype correlations and 4) investigate the use of the HumanHap550 platform for analysis of chromosome deletions. Deletions ranged from 95kb to 14.62Mb, and all of the breakpoints were unique. Eleven patients had deletions between 95kb and 4Mb and these individuals had normal development, with no anomalies outside of those associated with Alagille syndrome. The proximal and distal boundaries of these eleven deletions constitute a 5.4MB region, and we propose that haploinsufficiency for only 1 of the 12 genes in this region causes phenotypic abnormalities. This defines the JAG1 associated critical region, in which deletions do not confer findings other than those associated with Alagille syndrome. The other 10 patients had deletions between 3.28Mb and 14.62Mb, which extended outside the critical region, and notably, all of these patients, had developmental delay. This group had other findings such as autism, scoliosis and bifid uvula. We identified 47 additional polymorphic genome-wide copy number variants (>20 SNPs), with 0–5 variants called per patient. Deletions of the short arm of chromosome 20 are associated with relatively mild and limited clinical anomalies. The use of SNP arrays provides accurate high-resolution definition of genomic abnormalities.
PMCID: PMC2650004  PMID: 19058200
SNP array analysis; 20p deletion; copy number variants; Alagille syndrome; haploinsufficiency; JAG1
8.  Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease 
Nature genetics  2008;40(10):1211-1215.
Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn’s disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 × 10−8 and 6.95 × 10−8, respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 × 10−8; OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.
PMCID: PMC2770437  PMID: 18758464

Results 1-8 (8)