Clinical and genetic analysis in Chinese children with Alagille syndrome

doi:10.21203/rs.3.rs-1765237/v1

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Clinical and genetic analysis in Chinese children with Alagille syndrome

https://doi.org/10.21203/rs.3.rs-1765237/v1

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Background: Alagille syndrome (ALGS) is a multisystem disorder with changeable clinical penetrance. The genes responsible for this disease are JAGGED1 (JAG1) and NOTCH2. Clinical data of this disease is limited in China. The purpose of this study was to enrich the present data of Chinese children with Alagille syndrome by summarizing clinical characteristics and genetic variation of the cases.

Case summary: From January 2011 to February 2022, 10 children were diagnosed with ALGS. The organs involved in ALGS were as follows: liver (10, 100%); heart (7, 70%); characteristic facial features (7, 70%); skeleton (4, 40%); brain (1,10%) and kidney (3, 30%). Four patients (40%) were underweight. The main clinical manifestations were cholestasis, heart disease, and facial features. The median total bilirubin, direct bilirubin, and total bile acid were 138.75 mmol/L (normal, 3.4–20.5 mmol/L), 107.25 mmol/L (normal, 0–8.6 mmol/L), and 110.65 mmol/L (normal, 0.5–10.0 mmol/L), respectively. The median value of gamma-glutamyltranspeptidase was 223 U/L (normal, 9–64 U/L). Six (60%) children had hypercholesteremia. Eight different JAG1 gene variations and one NOTCH2 gene pathogenic variant in the 10 Chinese ALGS patients were identified.

Conclusion: Cholestasis was the most common initial presenting symptom in Chinese ALGS pediatric patients. Pathogenic variants in JAG1 and NOTCH2 are the primary mutations in Chinese children with ALGS, but we had our own unique variants spectrum. ALGS should be considered for cholestasis in infants and young children, especially those with multi-organ abnormalities.

Alagille syndrome

clinical manifestation

genetic analysis

China

Alagille syndrome (ALGS) is a multisystem disease. The main organs involved are liver, heart, eyes, skeleton, face, kidneys, and vasculature. With the development of molecular diagnostic technology, the incidence is likely 1 in 30,000 live births^[1]. At present, there is no epidemiological data on this disease in China.

ALGS is an autosomal dominant disorder. 94% of ALGS cases are due by pathogenic variants in JAG1 gene encoding the JAGGED1 protein, 1.5% by pathogenic variants in the NOTCH2 gene, and 4.5% by unknown pathogenic genes^[2]. In general, genetic confirmation is necessary because clinical presentation and disease severity are highly variable ^[3].

Although pathogenic variants causing ALGS have now been identified, the lack of genotype-phenotype correlation makes diagnosis of the disease difficult^[4]. Some studies have reported clinical and pathologic characteristics and gene variations of ALGS. Clinical data for Chinese ALGS patients is limited. We summarized the clinical features of ALGS in our hospital. Genetic pathogenic variants in Chinese children with ALGS were also analyzed. We hope that our work will further our understanding of ALGS disease in China, expand the known pathogenic gene pathogenic variant spectrum of ALGS, and provide assistance for diagnosis and treatment of children, as well as family genetic counseling and prenatal diagnosis.

Clinical data of patients diagnosed with ALGS in our hospital from January 2011 to February 2022 were retrospectively analyzed. Some patients initially presented to the local clinic for “jaundice”. They were transferred to our hospital soon after evaluation of their condition. To exclude extrahepatic disorders such as biliary atresia (BA), and infectious and metabolic disorders, we completed a series of tests including blood ammonia, lactic acid and blood glucose monitoring, blood gas ion analysis, bacterial culture, viral serology, thyroid function and serum amino acid analysis. Urine specimens were reserved for routine examination, cytomegalovirus nucleic acid detection and organic acid analysis. Imaging examinations included liver and spleen ultrasonic and magnetic resonance cholangiopancreatography examinations.

ALGS should be suspected in individuals with histological observation of bile duct paucity (decreased bile duct-to-portal tract ratio) on liver biopsy and three of the following five major clinical features: cholestasis, cardiac defect (cardiac auscultation and echocardiography), skeletal abnormalities (chest radiograph), ophthalmologic abnormalities (subspecialty consultation and slit lamp examination), and characteristic facial features (triangular face with a broad forehead and pointed chin, bulbous tip of the nose, deeply set eyes, and hypertelorism)^[5]. Most parents were reluctant to undergo liver biopsy because it is an invasive procedure. Liver biopsies were performed in only two cases in this study. All children had a heterozygous pathogenic variant in JAG1 or NOTCH2 identified by molecular genetic testing.

The data summarized included demographic characteristics (e.g., age, gender, weight), organs involved, liver function [alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltranspeptidase (GGT), serum total bilirubin (TBil), direct bilirubin (DB), total bile acid (TBA)], total cholesterol (TC), and molecular diagnosis of the genetic pathogenic variant.

Pathogenic Variant Analysis

Blood samples were obtained from the children and their parents. Genomic DNA was extracted using the blood genomic DNA extraction kit (MyGenostics Co., Ltd., Beijing). Targeted regions were amplified, purified and sequenced by high-throughput sequencing with Nextseq 500 (Illumina, San Diego, California, USA). Sequencing was performed by Beijing MyGenostics Medicine Research Center Co. Ltd. (Beijing, China). The databases for MAF annotation include 1,000 genomes, dbSNP, ESP, ExAC, and MyGenostics in-house MAFs database. Protein products structure variation were predicted by Provean, Sift, Polypen2_hdiv, Polypen2_hvar, Mutationtaster, M-Cap, and Revel software packages. As a prioritized pathogenicity annotation to the ACMG guidelines, OMIM, HGMD, and ClinVar databases were used to evaluate the pathogenicity of each variant. MaxEntScan, dbscSNV, and GTAG software packages were used to predict functional changes of variants on the splicing sites.

For statistical analysis, values are presented as the median and categorical data are presented as number and percentage.

There were 10 children in this study (eight boys and two girls), with a median age of 2.5 months (age range, 1–72 months). The organs involved in ALGS were as follows: liver (10, 100%): cholestasis (8, 80%), hepatomegaly (7, 70%), and simple hepatic dysfunction (abnormally elevated transaminases, > 2 times the normal value) (2, 20%); heart (7, 70%): aortic dysplasia (1, 14.3%), aortic stenosis (1, 14.3%), pulmonary artery stenosis (3, 42.8%), atrial septal defect (1, 14.3%), ventricular septal defect (1, 14.3%); characteristic facial features (7, 70%); epileptic seizure (1, 10%); and butterfly vertebrae (4, 40%). Three children (30%) had kidney involvement: renal ultrasound revealed rough renal parenchyma in 2 children, and hydronephrosis of the left kidney in the other child. Routine urine examination showed no abnormality. No children had ophthalmologic abnormalities. Six children (60%) had hypercholesteremia [median value, 6.02 mmol/L (normal, 3.36–5.69 mmol/L)]. Four children (40%) were below the 3rd percentile in weight for their age. The median total bilirubin, direct bilirubin, and total bile acid were 138.75 µmol/L (normal, 3.4–20.5 µmol/L), 107.25 µmol/L (normal, 0–8.6 µmol/L), and 110.65 µmol/L (normal, 0.5–10.0 µmol/L), respectively. The median value of gamma-glutamyltranspeptidase (GGT) in the 10 children was 223 U/L (normal, 9–64 U/L). One patient’s liver pathology showed intrahepatic bile duct paucity and giant cell hepatitis. The other case’s pathology of liver showed ductular proliferation (Tables 1 and 2).

Table 1

Demographic and clinical characteristics of 10 children with Alagilla syndrome. N = 10
Age (months)			2.5(1–72)
Gender (n, %)
		Male	8(80%)
		Female	2(20%)
Weight (kg)			5.05(3.72–18.8)
Clinical symptoms (n, %)
		Hepatic Features	10(100%)
		Cardiac Features	7(70%)
		Facial Features	7(70%)
		Ocular Features	0(0)
		Skeletal Features	4(40%)
		Renal Features	3(30%)
		hypercholesteremia	6(60%)
		underweight	4(40%)
		epileptic seizure	1 (10%)
Liver		function
		Total bilirubin(umol/L) (normal, 3.4–20.5 umol/L),	138.75(6.2-183.6)
		Direct bilirubin(umol/L) (normal, 0–8.6 umol/L)	107.25(2.4-148.3)
		Total bile acid(umol/L) (normal, 0.5–10.0 umol/L)	110.65(6.7-481.2)
		gamma-glutamyltranspeptidase(U/L) (normal, 9–64 U/L)	223(34-1139)
		Total cholesterol(mmol/L) (normal, 3.36-5.69mmol/L)	6.02(3.64–7.65)
Genetic variation
	JAG1 (n, %)		9(90%)
	NOTCH2 (n, %)		1(10%)

Table 2

Case series of 10 children with Alagille syndrome
Patient	Age(m)/ Gender	Weight (kg)	Organs involved	Liver function						TC (mmol/L) (3.36–5.69)	Liver biopsy	Genetic variation
Patient	Age(m)/ Gender	Weight (kg)	Organs involved	ALT (U/L) (0–40)	AST (U/L) (5–34)	GGT (U/L) (9–64)	TBil (umol/l) (3.4–20.5)	DB (umol/l) (0-8.6)	TBA (umol/l) (0.5–10.0)	TC (mmol/L) (3.36–5.69)	Liver biopsy	Genetic variation
1	1/F	4.3	cholestasis, hepatomegaly aortic dysplasia butterfly vertebrae renal parenchymal roughness	137	154	177	146.8	120.6	99.5	6.11	N	NOTCH2
2	2/M	3.8	cholestasis, hepatomegaly supravalvular aortic stenosis butterfly vertebrae facial features	88	211	1139	127.7	104.3	105.4	6.25	N	JAG1
3	2/M	3.72	cholestasis, hepatomegaly pulmonary artery stenosis facial features renal parenchymal roughness	439	576	34	181.1	141.0	123.8	4.25	intrahepatic bile duct paucity. giant cell hepatitis	JAG1
4	72/M	18.8	hepatic dysfunction facial features butterfly vertebrae hydronephrosis of the left kidney	98	86	117	6.2	2.4	6.7	3.64	N	JAG1
5	4/M	5.6	cholestasis, hepatomegaly atrial septal defect facial features	54	117	613	160.7	135.3	481.2	7.48	N	JAG1
6	3/M	5.4	cholestasis, hepatomegaly ventricular septal defect facial features epilepsy	253	347	106	130.7	110.2	135.5	4.05	N	JAG1
7	1/M	4.55	cholestasis, hepatomegaly pulmonary artery stenosis	37	63	157	106.7	48.7	159.9	7.65	Ductular proliferation	JAG1
8	3/F	6.3	hepatic dysfunction facial features	552	250	746	18.1	13.7	32.4	6.05	N	JAG1
9	6/M	8.0	cholestasis, hepatomegaly facial features	41	69	269	146.8	83.4	92.1	5.99	N	JAG1
10	1/M	4.7	cholestasis, acholic stool Common bile duct dysplasia, pulmonary artery stenosis, butterfly vertebrae	217	230	625	183.6	148.3	115.9	4.41	N	JAG1

Results of the genetic analyses are summarized in Table 3. Alterations of the JAG1 gene were identified in nine patients, and the NOTCH2 gene was sequenced in one. Eight distinct JAG1 pathogenic variants were identified (cases #2 and #8 had the same gene pathogenic variant): six were novel and included five nonsense pathogenic variants (55.6%), three frameshift pathogenic variants (33.3%), and one splicing pathogenic variant (11.1%). The pathogenic variants were located in the seven exons (6, 7, 11,12, 14, 23 and 25) that constitute the coding region of the JAG1 gene. The novel variation of NOTCH2 was the nonsense pathogenic variant c.3928C > T in exon24.

Table 3

Genetic traits of children with Alagille syndrome
Patient	Gene	Exon	Genetic mutation information	mutation type	Homozygous/Heterozygous	Family results	ACMG Pathogenicity analysis
1	NOTCH2	exon24	c.3928C > T p.Q1310X	nonsense	heterozygous	mother	Likely pathogenic
2	JAG1	exon23	c.2698C > T p.R900X	nonsense	heterozygous	spontaneous variant	pathogenic
3	JAG1	exon12	c.1464delC p.I488Mfs*10	frameshift	heterozygous	spontaneous variant	pathogenic
4	JAG1	exon25	c.3094_3095delAC p.T1032fs1	frameshift	heterozygous	spontaneous variant	pathogenic
5	JAG1	exon14	c.1853delA p.N618Tfs*125	frameshift	heterozygous	spontaneous variant	pathogenic
6	JAG1	exon6	c.2080A > T p.K694X	nonsense	heterozygous	spontaneous variant	pathogenic
7	JAG1	exon11	c.1395 + 3A > G splicing	splicing	heterozygous	mother	Likely pathogenic
8	JAG1	exon23	c.2698C > T p.R900X	nonsense	heterozygous	spontaneous variant	pathogenic
9	JAG1	exon12	c.1437T > A p.Y479X	nonsense	heterozygous	spontaneous variant	pahogenic
10	JAG1	exon7	c.960T > G p.Y320X	nonsense	heterozygous	spontaneous variant	pahogenic

Cholestasis is a key clinical feature that is usually present in the first 3 months ^[6]. In our retrospective study, the vast majority (8/10, 80%) of children were admitted to hospital with cholestasis. The most conserved feature of ALGS is bile duct paucity. Liver histology typically reveals a reduction in the concentration of intrahepatic bile ducts (bile duct to portal tract ratio < 0.4)^[7]. As few as 60% of patients < 6 months showed paucity, whereas it was commonly found in 95% of infants aged > 6 months^{[6, 8]}. However, the paucity tend is uncertain and controversy still exists. More clinical data are certainly needed for it.

Currently, there is a growing consensus that liver biopsy is not required if clinical biochemical evidence shows cholestasis and other characteristics of ALGS^[8]. This tendency prevents pediatric patients from undergoing an invasive liver biopsy for definitive diagnosis. In our study, liver biopsies had been performed for only two cases, but this did not affect diagnosis. Typical pathology is helpful for diagnosis of ALGS, but the detection of typical clinical manifestations and gene mutations have decreased clinician dependency on pathology.

The most common differential diagnosis of ALGS is BA. BA is characterized by significant small bile duct hyperplasia. Ductular hyperplasia may also occur in ALGS patients, but it is milder than BA^{[9, 10]}. The result of liver biopsy of our case# 7 was ductular proliferation. However, liver ultrasound and magnetic resonance cholangiopancreatography did not find the typical changes of BA. Case#10 showed acholic stool and even liver ultrasound suggested common bile duct dysplasia. However, both children had cardiac problems. The butterfly vertebrae in case #10 was typical. Combined with the genetic test, ALGS was confirmed.

Kamath et al. reported that serum bile salts can remain elevated even when hyperbilirubinemia has been resolved^[11]. Case #8 in the study showed normal total and direct bilirubin, but total bile acid remained elevated. GGT is also commonly elevated. The median value of GGT in the ten children in this study was 223 U/L (normal, 9–64 U/L). Case #3 was a 2-month-old boy with a normal GGT level (34 U/L). In children with normal GGT levels, familial progressive cholestasis is first suspected. However, this child also had pulmonary artery stenosis, facial features associated with ALGS. A liver biopsy suggested typical intrahepatic bile duct paucity. His JAG1 pathogenic variant was novel (c.1464delC). Functional validation of the gene is ongoing. There are only a few reports of normal GGT levels in ALGS^[10]. We speculate that normal GGT may represent an early stage ALGS in children. As the disease progresses, GGT increases, resulting in a pathological state.

Several larger descriptive studies showed renal and vascular abnormalities in many patients. Renal symptoms were not uncommon in our cases and were seen in three children. Rough renal parenchyma or hydronephrosis of the left kidney was found by ultrasound. Epilepsy was a unique symptom of Case #6, which is rare in ALGS. Extracranial or intracranial vascular abnormalities could be the cause, although we found no evidence for this.

Ocular abnormalities are one of the major features in initial diagnosis of ALGS. Surprisingly, none of the children in our study showed ocular symptoms. We thought there may be two reasons. First, posterior embryotoxon is so rare that our ophthalmologists could not identify it accurately; second, we hypothesize that this may be a feature of the Chinese children with ALGS. More cases are needed to confirm it.

In ALGS, 94–95% of patients have a heterozygous pathogenic variant in JAG1, and 1–2% of patients have a heterozygous pathogenic variant in NOTCH2^[12]. Pathogenic variants in the JAG1 gene were identified in nine patients (90%): five nonsense pathogenic variants (55.6%), three frameshift pathogenic variants (33.3%), and one splicing pathogenic variant (11.1%). The only identified NOTCH2 pathogenic variant was nonsense. Significantly, most of these genetic pathogenic variants have not been reported, indicating our cases may have a unique variants spectrum.

ALGS cases with JAG1 pathogenic variants usually present facial dysmorphism, heart involvement compared to NOTCH2^{[13, 14]}. Renal abnormalities may be more common in cases with NOTCH2 pathogenic variants^[15]. However, many studies have reported no clear correlation between genotype and phenotype in this disease. The phenotypic variability was seen among patients with the same pathogenic variants^[16]. This type of variability has been associated with liver disease, with clinical manifestations ranging from mild liver function abnormalities to severe cholestasis ^[17]. In the present study, cases #2 and #8 had the same genetic pathogenic variant although the clinical manifestations differed. This supports the changeable phenotypic penetrance of ALGS. Some studies have suggested that this may be due to the existence of other genes as genetic modifiers, such as the Fringe protein family, including LFNG, RFN, and MFNG, which can alter NOTCH signaling by regulating glycosyltransferase activity. THBS2 has also been considered a potential genetic modifier^{[18, 19]}.

The system of graded diagnosis and treatment in China is not good enough. Almost all children with severe cholestasis will choose the best hospital for the first diagnosis. Through the study, we have realized that the primary pediatricians’ cognition of ALGS is insufficient, which is why we wrote this manuscript.

The characteristic of our study is that pathogenic variants in JAG1 and NOTCH2 are the primary variants in Chinese children with ALGS, but we had our own unique variants spectrum. The other surprising finding was that none of the patients had any ocular symptoms. Whether this is a feature of Chinese children with ALGS is unknown. We need more cases to prove it. ALGS should be considered for cholestasis in infants and young children, especially those with multi-organ abnormalities.

Ethics approval and consent to participate：The study was approved by the Ethics Committee of Shengjing Hospital of China Medical University（2021PS857K). All methods were performed in accordance with the Declarations of Helsinki guidelines and regulations. None information or images of this manuscript can identify the participants. As a retrospective study, the informed consent statement was waived by the Ethics Committee of Shengjing Hospital of China Medical University.

Consent for publication: None information or images of this manuscript can identify the participants. Not applicable.

Availability of data and materials: The datasets generated and analysed during the current study are not publicly available due the request to upload the data didn't approve by the Ethics Committee of Shengjing Hospital of China Medical University, but are available from the corresponding author on reasonable request.

Competing interests: The authors report no conflicts of interest.

Funding: None

Acknowledgements：We thank International Science Editing for editing this manuscript.

Authors’ contributions: Dr. Ying Chen had primary responsibility for protocol development, outcome assessment, preliminary data analysis and drafting the manuscript. Pro. Xu Teng and Mei Sun supervised the design and execution of the study and revised the article critically for important intellectual content. All authors read and approved the final manuscript.

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Clinical and genetic analysis in Chinese children with Alagille syndrome

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Abstract

Introduction

Materials And Methods

Pathogenic Variant Analysis

Results

Discussion

Declarations

References

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