A Retrospective Study of Clinical and Genetic Features in a Long-Term Cohort of Mexican Children with Alagille Syndrome
Abstract
1. Introduction
2. Results
2.1. Study Population
2.2. Clinical Manifestations
2.3. Histopathology
2.4. Genetic Findings
2.5. Treatment and Outcomes
3. Discussion
3.1. Hepatic Manifestations
3.2. Extrahepatic Manifestations
3.3. Notable Phenotypes
3.4. Genetic Findings
3.5. Perspectives
3.6. Strengths and Limitations
4. Materials and Methods
4.1. Study Design, Population, and Data Collection
4.2. Genetic Analysis
4.3. Liver Histopathology
4.4. Other Assessments
4.5. Statistical Analysis
4.6. Ethical Considerations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACMG | American College of Medical Genetics and Genomics |
AI | Auricles with adequate implantation |
ALGS | Alagille syndrome |
ALT | Alanine aminotransferase |
ASD | Atrial septal defect |
AST | Aspartate aminotransferase |
BFH | Broad forehead |
BNT | Bulbous nasal tip |
CNV | Copy number variant |
DB | Direct bilirubin |
Dol | Dolichocephaly |
DSEs | Deep-set eyes |
EF | Epicanthus |
EVs | Esophageal varices |
GGT | Gamma-glutamyl transferase |
H&E | Hematoxylin and eosin |
HypT | Hypertelorism |
ICHU | Inferior crus of helix underdevelopment |
IBAT | Ileal bile acid transporter |
MRI | Magnetic resonance imaging |
NGS | Next-generation sequencing |
PAS | Pulmonary artery stenosis |
PDA | Patent ductus arteriosus |
PE | Prominent ears |
PC | Pointed chin |
PFO | Patent foramen ovale |
PM | Pathogenic moderate |
PP | Pathogenic supporting |
PS | Pathogenic strong (ACMG classification evidence code) |
PVS | Pathogenic very strong (ACMG classification evidence code) |
RTA | Renal tubular acidosis |
SVPS | Supravalvular pulmonary stenosis |
TB | Total bilirubin |
Tc | Telecanthus |
TUL | Thin upper lip vermilion |
TOF | Tetralogy of Fallot |
UPF | Up-slanting palpebral fissures |
UPJ | Ureteropelvic junction |
VSD | Ventricular septal defect |
VUR | Vesicoureteral reflux |
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Patient | Sex | Age at Onset | Age at Diagnosis | Age at Last Follow-Up | Family History | Neonatal Cholestasis (n = 17) | Cardiovascular Findings (n = 15) | Renal Findings (n = 13) | Vascular Findings (n = 11) | Skeletal Finding (n = 14) | Ophthalmic Findings (n = 17) | Facial Features (n = 10) | Pruritus (n = 5) | Age at Transplant (If Performed) (n = 15) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
P1 | Male | - | 1 mo | 11 y | No | Yes | PAS | No | No | Butterfly vertebrae | Retinal pigmentary changes, right exotropia | BFH, HypT, PC | - | 6 y |
P2 | Female | 3 mo | 3 y | 19 y | No | Yes | PAS | Double right collecting system | No | Scoliosis | No | - | No | 9 y |
P3 | Male | 2 mo | 2 mo | 9 y | No | Yes | Crossed pulmonary arteries | Left renal atrophy, right solitary kidney | No | Hemivertebra | Posterior embryotoxon | - | - | Unspecified |
P4 | Male | - | 3 mo | 2 y | No | Yes, with intrahepatic portal hypertension | VSD | - | No | No | No | - | - | Waiting list |
P5 | Male | - | 3 mo | 10 y | Mother with suspected but unconfirmed ALGS | Yes | PAS | No | No | Scoliosis | Posterior embryotoxon | BFH, DSE, PC | No | Waiting list |
P6 | Male | 15 d | NA | 2 y | No | Yes | - | - | - | - | - | - | - | Waiting list |
P7 | Female | - | - | 17 y | No | Yes | PA, tricuspid insufficiency | No | - | Butterfly vertebrae | Posterior embryotoxon | Tc, PC | - | Waiting list |
P8 | Female | 1 mo | - | 6 y | No | Yes | PAS | No | EV | Butterfly vertebrae | Posterior embryotoxon | BFH, DSE, PC | - | Waiting list |
P9 | Male | - | - | - | - | - | - | - | - | - | - | - | - | - |
P10 | Male | - | - | - | - | - | - | - | - | - | - | - | - | - |
P11 | Male | - | - | Deceased | - | - | - | - | - | - | - | - | - | - |
P12 | Male | - | - | - | - | - | - | - | - | - | - | - | - | - |
P13 | Female | - | - | 9 y | No | No | ASD | No | - | Butterfly vertebrae | Posterior embryotoxon, blue sclerae, deep-set eyes | - | - | - |
P14 | Male | 1 w | 1 w | - | No | Yes | PAS | No | - | Butterfly vertebrae | No | No | - | 0 y, deceased 2 weeks after transplant |
P15 | Male | 2 mo | 2 mo | 6 y | Yes: one parent and a parent’s cousin | Yes | SVPS, PAS, PFO, PDA | VUR, post-operative left UPJ stenosis, RTA | No | Butterfly vertebrae | No | BFH, DSE, PE, BNT, PC | - | Waiting list |
P16 | Male | 2 mo | 2 mo | 1 y | No | Yes | VSD | No | No | No | No | Dol, BFH, SE, UPF, EF, DSE, BNT | - | Waiting list |
P17 | Male | 15 d | 3 y | - | Yes, one of the parents | Yes | PDA | No | No | No | Posterior embryotoxon | SE, UPF, HypT, BNT, TUL, PC, AI, ICHU | - | Waiting list |
P18 | Female | - | - | 1 y | Yes: two paternal cousins deceased at age 2 with unspecified hepatopathy | No | TOF with pulmonary valve agenesis | No | No | Butterfly vertebrae | Posterior embryotoxon | DSE, PC | Yes, on treatment with cholestyramine | Waiting list |
P19 | Male | - | - | - | - | - | - | - | - | - | Lisch Nodules | - | - | No |
P20 | Male | 4 y | - | No | No | PAS | - | - | - | Posterior embryotoxon | - | Yes, on treatment with ursodeoxycholic acid | - | |
P21 | Male | - | - | Deceased | No | No | - | No | No | No | Posterior embryotoxon | - | - | - |
P22 | Male | 2 mo | 5 mo | 5 mo | No | Yes | PAS | - | - | - | Visual immaturity due to delayed conduction | BFH, HypT, PC | No | Waiting list |
Patient | Liver Biopsy |
---|---|
P1 | Reduced portal spaces and bile ducts; no cholangial proliferation |
P2 | Decreased intrahepatic bile ducts, bile retention in hepatocytes, dilated sinusoids |
P3 | Intrahepatic bile duct hypoplasia |
P4 | Partial biliary flow obstruction, stage 3 fibrosis |
P7 | Decreased interlobular bile ducts |
P13 | Minimal changes suggestive of portal hypertension secondary to efferent flow obstruction |
P14 | No significant changes |
P16 | Giant cell hepatitis, lobular disarray, cholestasis, mild portal fibrosis, no ductular proliferation, no microorganisms detected |
P17 | Expanded portal spaces with lymphoplasmacytic infiltrate, fibrosis with septal formation, biliary pigment in hepatocytes |
P18 | Bile duct paucity, giant cell hepatitis |
P21 | Fibrosis |
P22 | Bile duct hypoplasia, cholangial proliferation, intracanalicular and intracytoplasmic cholestasis, scattered apoptotic cells |
Patient | Gene | NM ID | cDNA | Amino Acid Change | rsID | Mutation Type | Classification | Previous Reports in the Literature (PMID) |
---|---|---|---|---|---|---|---|---|
P1 | JAG1 | NM_000214.3 (JAG1) | c.550C>T | p.Arg184Cys | rs121918350 | Missense | Likely Pathogenic (PM1, PM2, PM5, PP2, PP3, PP4, PP5) | 24748328 |
P3 | JAG1 | NM_000214.3 (JAG1) | c.295A>C | p.Thr99Pro | - | Missense | Likely Pathogenic (PM1, PM2, PM5, PP2, PP3, PP4) | Novel |
P4 | JAG1 | NM_000214.3 (JAG1) | c.743delC | p.Pro248Glnfs*164 | - | Frameshift | Pathogenic (PVS1, PS3, PM2, PP4) | Novel |
P5 | JAG1 | NM_000214.3 (JAG1) | c.2392delG | p.Val798Trpfs*22 | - | Frameshift | Pathogenic (PVS1, PS3, PM2, PP4) | Novel |
P7 | JAG1 | NM_000214.3 (JAG1) | c.1308C>A | p.Cys436* | rs764485729 | Nonsense | Pathogenic (PVS1, PM2, PP2, PP4) | 25676721 |
P8 | JAG1 | NM_000214.3 (JAG1) | c.220T>G | p.Tyr74Asp | - | Missense | Likely pathogenic (PM1, PM2, PM5, PP3, PP4) | - |
P10 | JAG1 | NM_000214.3 (JAG1) | c.2122_2125delCAGT | p.Gln708Valfs*34 | rs727504412 | Frameshift | Pathogenic (PVS1, PS3, PM2, PP3, PP4, PP5) | 25676721 |
P11 | JAG1 | NM_000214.3 (JAG1) | c.439+1G>A | - | rs863223648 | Splice donor variant | Pathogenic (PVS1, PM1, PM2, PP3, PP4, PP5) | 24748328 |
P12 | JAG1 | NM_000214.3 (JAG1) | c.2939G>A | p.Cys980Tyr | - | Missense | Likely pathogenic (PM1, PM2, PM5, PP2, PP3, PP4) | Novel |
P13 | JAG1 | NM_000214.3 (JAG1) | c.890del | p.Gly270AspfsTer145 | - | Frameshift | Pathogenic (PVS1, PS3, PM1, PM2, PP4) | Novel |
P14 | JAG1 | NM_000214.3 (JAG1) | c.91dup | p.Ala31Glyfs*42 | - | Frameshift | Pathogenic (PVS1, PS3, PM2, PP4). | Novel |
P15 | JAG1 | NM_000214.3 (JAG1) | c.2956_2957dup | p.Leu986fs | rs2122595849 | Frameshift | Pathogenic (PVS1, PS3 PM2, PP4, PP5). | - |
P16 | JAG1 | NM_000214.3 (JAG1) | c.2122_2125del | p.Gln708Valfs*34 | rs727504412 | Frameshift | Pathogenic (PVS1, PS3, PM2, PP4, PP5) | 15712272 |
P17 | JAG1 | NM_000214.3 (JAG1) | c.2122_2125del | p.Gln708Valfs*34 | rs727504412 | Frameshift | Pathogenic (PVS1, PS3, PM2, PP4, PP5) | 22488849 |
P18 | JAG1 | NM_000214.3 (JAG1) | c.2225_2226delTA | p.Ile742SerfsTer5 | rs1555828209 | Frameshift | Pathogenic (PVS1, PS3, PM2, PP4, PP5). | 21752016 |
P19 | JAG1 | NM_000214.3 (JAG1) | c.1977G>A | p.Trp659* | rs1600182107 | Nonsense | Pathogenic (PVS1, PS3, PM1, PM2, PP4, PP5) | 12497640 |
P20 | JAG1 | NM_000214.3 (JAG1) | c.3048+1G>T | - | rs876661121 | Splice donor variant | Pathogenic (PVS1, PM2, PP3, PP4, PP5) | 31343788 |
P21 | NOTCH2 | NM_024408.4 (NOTCH2) | c.3878G>A | p.Arg1293His | rs201968231 | Missense | Variant of Uncertain Significance (PM1, PM2, PP4) | - |
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Vázquez-Frias, R.; Varela-Fascinetto, G.; Acosta-Rodríguez-Bueno, C.P.; Consuelo, A.; Carrillo, A.; Reyes-Apodaca, M.; Moreno-Salgado, R.; López-Valdez, J.; Hernández-Chávez, E.; González-Ortiz, B.; et al. A Retrospective Study of Clinical and Genetic Features in a Long-Term Cohort of Mexican Children with Alagille Syndrome. Int. J. Mol. Sci. 2025, 26, 7626. https://doi.org/10.3390/ijms26157626
Vázquez-Frias R, Varela-Fascinetto G, Acosta-Rodríguez-Bueno CP, Consuelo A, Carrillo A, Reyes-Apodaca M, Moreno-Salgado R, López-Valdez J, Hernández-Chávez E, González-Ortiz B, et al. A Retrospective Study of Clinical and Genetic Features in a Long-Term Cohort of Mexican Children with Alagille Syndrome. International Journal of Molecular Sciences. 2025; 26(15):7626. https://doi.org/10.3390/ijms26157626
Chicago/Turabian StyleVázquez-Frias, Rodrigo, Gustavo Varela-Fascinetto, Carlos Patricio Acosta-Rodríguez-Bueno, Alejandra Consuelo, Ariel Carrillo, Magali Reyes-Apodaca, Rodrigo Moreno-Salgado, Jaime López-Valdez, Elizabeth Hernández-Chávez, Beatriz González-Ortiz, and et al. 2025. "A Retrospective Study of Clinical and Genetic Features in a Long-Term Cohort of Mexican Children with Alagille Syndrome" International Journal of Molecular Sciences 26, no. 15: 7626. https://doi.org/10.3390/ijms26157626
APA StyleVázquez-Frias, R., Varela-Fascinetto, G., Acosta-Rodríguez-Bueno, C. P., Consuelo, A., Carrillo, A., Reyes-Apodaca, M., Moreno-Salgado, R., López-Valdez, J., Hernández-Chávez, E., González-Ortiz, B., Cadena-León, J. F., Villalpando-Carrión, S., Worona-Dibner, L., Martínez-Montoya, V., Cerón-Muñiz, A., Ramírez-Ramírez, E., & Barragán-Arévalo, T. (2025). A Retrospective Study of Clinical and Genetic Features in a Long-Term Cohort of Mexican Children with Alagille Syndrome. International Journal of Molecular Sciences, 26(15), 7626. https://doi.org/10.3390/ijms26157626