Gaucher Disease

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: GBA (HGNC:4177)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 12/08/2022
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
GBA	Gaucher disease (0018150)	608013	N/A - Insufficient evidence: early rule-out
GBA	Gaucher disease (0018150)	231005	N/A - Insufficient evidence: early rule-out
GBA	Gaucher disease (0018150)	231000	N/A - Insufficient evidence: early rule-out
GBA	Gaucher disease (0018150)	230800	N/A - Insufficient evidence: early rule-out
GBA	Gaucher disease (0018150)	230900	Definitive Actionability

Actionability Assertion Rationale

• The computed assertion was strong but there is significant evidence that surveillance for this condition identifies people for whom there is a highly effective therapy, despite the lack of penetrance data in an unselected population. The determination of the type of Gaucher disease is made on clinical evaluation. Randomized controlled trials are not likely to be forthcoming. This assertion is specific to the non-neurological manifestations. The group recognizes that there is no identified effective therapy for neurological manifestations. This topic has been assigned as assertion of definitive. Thus, this topic will not be updated unless it is renominated because of new evidence which could change the assertion.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity due to non-neurological manifestations (including hematological, visceral, and skeletal disease) / Referral to specialists for surveillance and initiation of enzyme replacement therapy, when indicated	2	3C	3A	2	10CA

Severity of Outcome

Prevalence of the Genetic Condition

Gaucher disease (GD) is pan-ethnic and has a frequency of 1/40,000 in the US. A recent systematic review of prevalence of GD reported a global birth prevalence of 1.5/100,00 live births, based on 16 studies covering 14 countries. The global prevalence was reported as 0.9/100,00 based on 4 European studies.

Type 1 affects 1/20,000-1/200,000 in the population worldwide. The disorder is most common among the Ashkenazi Jewish population, with a prevalence of 1/400-1/1000. Types 2 and 3 typically occur in <1/100,000 live births but may be more common in some countries.

Clinical Features (Signs / symptoms)

GD is a lysosomal storage disorder caused by a deficiency of glucocerebrosidase which results in the multisystemic accumulation of glucosylceramide-laden macrophages (Gaucher cells) in various tissues: spleen, liver, bone marrow, bone mineral, and less often the lungs, skin, eyes, kidneys, lymphatic system, and heart. The spectrum of clinical manifestations and symptoms includes hepatosplenomegaly (HSM), abdominal discomfort and distension, skeletal disease (e.g., bone pain, osteopenia, bone infarct, osteonecrosis, pathological fractures), cytopenia (e.g., thrombocytopenia, anemia), fatigue, excessive bleeding, increased risk of infections, cardiovascular complications, and pulmonary disease. Additional symptoms in children include failure to thrive, growth delay, and delayed puberty. Some forms of GD include central nervous system involvement. GD consists of a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. However, there are 3 classically recognized types of GD that are distinguished by the presence or absence of primary, progressive neurodegenerative disease, and therapeutic options:

• Type 1 (non-neuronopathic form) accounts for >90% of cases. It is characterized by bone disease, HSM, cytopenia, and pulmonary disease. Other features include secondary neurologic disease, immunologic and metabolic abnormalities, gallstones, and increased risk for multiple myeloma and Parkinson disease.

• Type 2 (acute neuronopathic form) accounts for about 5% of cases. It is the most severe form and is associated with HSM, cytopenia, pulmonary disease, and dermatologic changes. Primary neurological involvement is severe and can include bulbar and pyramidal signs, and cognitive impairment. A perinatal lethal subtype is associated with ichthyosis or collodion skin and nonimmune hydrops fetalis.

• Type 3 (subacute/chronic neuronopathic form) accounts for <5% of cases but is difficult to distinguish from type 2. It is associated with bone disease, HSM, cytopenia, and pulmonary disease. Primary neurological involvement is minimal and can include oculomotor apraxia, seizures, and progressive myoclonic epilepsy. A cardiovascular subtype is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia.

Natural History (Important subgroups & survival / recovery)

GD is a progressive disorder whose natural course and extent of disease is highly variable. In the absence of treatment, the natural course includes frequent complications such as bleeding, infection, lung disease, hematological and skeletal complications, liver failure, severe pulmonary disease, and high morbidity and mortality rates. GD-related bone disease is the most significant cause of morbidity and long-term disability.

Clinical presentation, age at onset, and disease course can vary by clinical type:

• Type 1 affects children and adults at any age, but 60% of individuals manifest symptoms in childhood and are diagnosed before 20 years of age. Some individuals are asymptomatic. Clinical presentation and disease progression vary, and survival may be normal depending on the severity of complications. Earlier onset correlates with more severe disease and a high risk of morbid complications. The early symptoms of type 1 tend to reflect the hematological aspects of the condition (cytopenia, and bleeding tendency). Bone disease can be acute and/or chronic and is typically the most painful and debilitating aspect of type 1.

• Type 2 has very severe infantile-onset systemic and CNS disease with early demise. Type 2 typically presents before age 2 years (sometimes in utero) and a rapidly progressive course with death by age 2 to 4 years, often due to lung failure.

• Type 3 typically presents before age 2 for somatic involvement. Neurological involvement may manifest at any age and is recognized at the time or after somatic findings. It has a more slowly progressive course than type 2 with survival into the 3rd or 4th decade.

Pregnancy can exacerbate preexisting symptoms and trigger new features in individuals with GD, especially for those who have not received therapy or whose manifestations have yet to be controlled by treatment. Some individuals are first diagnosed during pregnancy or soon after delivery. GD-specific complications during pregnancy, although rare, include increased HSM, new or worsening cytopenia that may lead to postpartum bleeding, possible increases in spontaneous abortion, postpartum infections and associated fever, and bone crises.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

< 1-2 in 100000

A recent systematic review of the prevalence of GD, including 2 European studies, reported the birth prevalence of type 1, type 2, and type 3 to be 1.5 (95% CI: 1.4-1.7), 0.2 (95% CI: 0.1-0.2), and 0.1 (95% CI: 0.1-0.1) per 100,000 live births, respectively.

Tier 1

>1-2 in 100

Registry studies, including up to 3337 individuals, report that 90-95% of individuals have type 1, ≤5% have type 2, and <5% have type 3.

Tier 3

Unknown

Recent studies indicate that in Europe, Canada, and the US the most prevalent form of GD is type 1. However, in Pakistan, India, Egypt, China, Japan, Sweden, and Poland types 2 and 3 may be more prevalent than type 1.

Tier 3

>1-2 in 100

The Ashkenazi Jewish population is estimated to have a carrier frequency between 1/14-1/17. Estimates of prevalence in other populations were not available. Given that a GBA pathogenic variant is detected in 99% of clinically diagnosed individuals with GD and the prevalence of GD is 1/40,000 in the US, then the carrier frequency can be estimated as 1/100.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

International registry data reported that of 1698 individuals with GD (94% had type 1), 79-87% had HSM. Histories of bone pain and radiological bone disease were reported in 63% and 94% of individuals, respectively. Cytopenia was present in 56-64%; with 15% demonstrating severe thrombocytopenia.

Tier 3

>= 40 %

A prospective evaluation of 95 individuals with type 1 (mean age 29 years, age range 7-66 years) identified pulmonary function abnormalities in 68%, chest radiographic abnormalities in 17%, and pulmonary hypertension in 3% of individuals.

Tier 3

>= 40 %

A systematic review of the effects of ERT on the growth of children and adolescents with type I that included 17 studies (mostly retrospective and non-controlled with small sample size), reported the following prior to initiation of ERT:

• Weight below the 5th percentile: 10-60% of individuals (5 studies)

• Height below the 5th percentile: 33-74% of individuals (7 studies, including one study with 702 individuals). One study reported that 50% of symptomatic children with type 1 are at or below the third percentile for height, and another 25% are shorter than expected based on their midparental height.

• Slow growth: 33-80% (7 studies)

• Pubertal delay: 60% (1 small study)

Tier 1

>= 40 %

A registry study of 887 children with type 1 GD reported that HSM and bone disease were each found in more than 80% of children at diagnosis. In untreated children, median spleen volumes were more than 20 times the normal size and median liver volumes were twice the normal size for the child’s age and weight. Anemia and moderate to severe thrombocytopenia were both found in approximately 40% of children. Approximately 80% of children had at least one skeletal abnormality at diagnosis.

Tier 3

>= 40 %

In a study of 131 children with neuronopathic GD (types 2 and 3), the most common manifestations were: inability to look to the extreme up or down (45%), abnormally slow object tracking (43%), convergent squint (36%), and ataxia (15-20%). Seizures and myoclonic seizures were reported in 16% and 2% of children, respectively.

Tier 3

>= 40 %

A case series following 34 children with GD (mostly type 3) for 7 years (median age 8.6 years; average duration of ERT 6.5 years) identified pulmonary manifestations in 59% of children, including 14 with recurrent chest infections, dyspnea, and wheezing. Of these children, four were admitted to intensive care and one died of severe pulmonary disease

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

GD is characterized by variable clinical expression, progression, severity, and life expectancy. Even individuals with the same genotype, including siblings and monozygotic twins, may show distinct patterns of disease. Individuals with GD with the same pathogenic variant may present in childhood or be asymptomatic throughout adult life. The broadest phenotypic spectrum in GD with respect to age of onset, rate of progression, and organs affected occurs in type 1

Tier 3

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/Gaucher.pdf

Individuals with GD should be treated by a multidisciplinary team with expertise in treating GD to assess disease course and effects of therapy. Ideally, children with GD should be managed at a center with expertise in GD or evaluated annually at such a center if they receive most of their care elsewhere. Managing the multisystemic signs and symptoms of GD should be individualized.

Tier 2

Enzyme replacement therapy (ERT) with recombinant glucocerebrosidase (imiglucerase, velaglucerase, or taliglucerase) is the current standard of care for symptomatic individuals with GD types 1 and 3 but has little effect on the course of disease in individuals with type 2 disease and is not recommended. ERT for individuals with type 3 GD is not approved in all countries.

• To initiate ERT in type 1, one or more of the following manifestations (signs or symptoms) must be present: hepatic, splenic (or prior splenectomy), cardiac, pulmonary, or renal compromise; cytopenia; low levels of platelets; pain or bone crisis; active bone disease; and/or slowed growth or growth failure and delayed puberty. In asymptomatic children with type 1, treatment is necessary only if signs or symptoms develop. Individuals may be asymptomatic, yet harbor significant disease manifestations such as cytopenia, HSM and osteopenia. These individuals should receive treatment to reverse disease manifestations.

• In children with type 1, early therapeutic intervention is important to attain growth potential and peak skeletal mass, and to avoid serious and irreversible manifestations of GD. Any child with disease manifestations should be treated.

• Individuals with type 3 GD based on clinical features, age of onset, biomarkers, family history, and genotype, should be offered treatment for somatic signs/symptoms as soon as possible after confirmed diagnosis. However, treatment may not be indicated for the most severely affected patients who experience disease progression and early demise despite maximal therapy.

• Children who require ERT need to continue therapy indefinitely to maintain their clinical improvements. Interruption in therapy is associated with relapse in hematologic and organ volume measures and is presumed to also result in relapse in skeletal parameters.

• Some manifestations do not respond to ERT: fibrous splenomegaly; osseous injury including secondary osteoarthritis, osteofibrosis, osteonecrosis, fracture, joint collapse, lytic lesions, and deformities due to vertebral compression; hepatic fibrosis; and lung fibrosis. While timely initiation of ERT can prevent these manifestations, some are irreversible once they occur.

• There is currently no evidence that ERT reverses, prevents, or slows neurological progression in individuals with GD.

Tier 2

Since GD is rare, it is difficult to obtain large numbers of individuals for high-quality studies. The availability of effective treatment makes randomized control trials (RCTs) ethically difficult to design and perform. Thus, most of the data on the effectiveness of ERT are derived from case series and registries. The most recent, most comprehensive evidence for the effectiveness of ERT is summarized below.

One systematic review of 51 longitudinal studies on ERT effectiveness (N ≥ 930 individuals of all ages), and the majority included only individuals with type 1 GD (80% of studies) and treatment-naïve individuals (62% of studies). The meta-analyses demonstrated significant improvement in hematological parameters, which were sustained up to 7 years. Significant reductions in liver and spleen sizes were observed up to 12 and 48 months, respectively.

Tier 1

ERT in children results in dramatic reduction of organ size and resolution of cytopenia. Registry data from 884 ERT-treated children showed that most of the hematologic benefits and approximately half of the HSM benefits occur during the first year of treatment.

• By 8 years of ERT:

- Hematologic manifestations (present in 50% or more at baseline) improved in 95-100%.

- Individuals demonstrated significant reductions in liver and spleen. Median liver volume was 2.0 multiples of normal (MN) predicted for body weight at baseline and improved to 1.1 MN. Median spleen volume at baseline was 23 MN and improved to 4.8 MN.

- Median height Z-scores significantly improved and by 8 years median height was similar to that of the general population.

• After 6.6 years, median BMD Z-scores were not substantially different from an age- and gender-specific reference population. Improvements were significant at 12 years.

• Ninety children reported bone crises before initiation of ERT, but after 2 years no new bone crises were reported.

Tier 1

Another registry study evaluated lumbar spine BMD in adults with type 1, comparing 160 adults who did not receive ERT (untreated) with 342 adults who received ERT alone. The study reported that although BMD Z-scores for both the untreated and treated groups were significantly lower than the healthy reference population at baseline, BMD only improved for those who received ERT. These improvements were significant over time (+0.132 Z-score units/year), approaching the reference population by 8 years.

Tier 2

The effects of ERT on hematological, visceral, and growth outcomes were evaluated in a registry study including 253 children and adolescents with type 3. During the first year of ERT there were marked decreases in the number of children with moderate or severe cytopenia and HSM. These improvements were maintained over 5 years. There was also acceleration in linear growth. Despite devastating disease at baseline, the probability of surviving for at least 5 years after starting ERT was 92%.

Tier 5

Oral substrate reduction therapy (SRT) with eliglustat may be used as first-line monotherapy for treatment of adults with type 1 GD who have a compatible CYP2D6 metabolism phenotype, as determined by CYP2D6 genotyping. SRT is not approved for children and should be avoided in individuals who are pregnant or are considering having a biological child. Physicians must carefully evaluate individuals with type 1 GD to determine their eligibility for eliglustat therapy, including the assessments of the following:

• CYP2D6 genotyping to determine metabolizer status. Eliglustat may be considered in individuals who are poor, intermediate, or extensive metabolizers (categories which apply to >90% of individuals with type 1 GD), but it cannot be used in those who are ultrarapid metabolizers.

• Concomitant medication use (e.g., CYP2D6 or CYP3A inhibitors, antiarrhythmic medications, QT-prolonging medications)

• Baseline electrocardiogram

• Presence of comorbidities

• Pregnancy, intent to have biological children in the near future (including becoming pregnant), and lactation.

Tier 2

A systematic review of the effectiveness of eliglustat for the treatment of type 1 GD included two randomized controlled trials (RCTs).

First RCT:

• Evaluated eliglustat versus placebo in 40 adults who were treatment-naïve or had a washout period of ≥9 months.

• Reported significant differences between eliglustat and placebo at 39 weeks in spleen and liver volume, platelet counts. and hemoglobin levels.

• Had a long-term treatment period of 234 weeks (4.5 years), where all efficacy outcomes improved, albeit only a small subset of participants had available data.

Second RCT:

• Included 160 adults whose symptoms were well-controlled with ERT who switched to eliglustat and were followed for 52-weeks.

• 85% of individuals who switched to eliglustat met hematologic and organ volume stability criteria compared to 94% of those who remained on ERT.

• Stability was maintained for 104 weeks in 87.8% of individuals treated with eliglustat.

• Eliglustat met the noninferiority criteria, but there was uncertainty in the noninferiority margin used in the analysis and concern of carry-over benefits from ERT.

Tier 1

A second systematic review, which included one extension study of 19 treatment-naive adults followed after a 52-week trial, reported a significant increase in hemoglobin over 8 years on ERT. For other outcomes, meta-analyses could only be done for treatment-experienced individuals (up to 3 studies per time point, up to 48 months follow-up). Platelet levels remained stable over time but did not improve; and liver and spleen were maintained at baseline size, but reduction was not significant.

Tier 1

The 8-year extension study of the Phase 2 trial of 19 treatment-naïve type 1 adults on eliglustat reported that mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean femur T-scores also increased. A Phase 3 dosing trial (156 predominantly adults, 85% previously treated with ERT) reported that mean and median bone marrow burden scores remained moderate and mean and median BMD remained in the normal range for up to 3.3 years

Tier 2

Recommendations for people with GD considering pregnancy or who are pregnant include:

• Pregnancy and its possible outcomes should be discussed with individuals with GD of childbearing age

• Bone involvement should be assessed before pregnancy.

• Therapeutic goals should be achieved before considering pregnancy.

• After delivery, individuals should be monitored for infection, bleeding, appearance of bone crises, and bone rarefaction.

• ERT after the first trimester is advised for all pregnant people with GD, but there is no definitive evidence whether ERT should be continued during pregnancy. ERT is also advised during breastfeeding. Continuation of ERT at the pre-pregnancy dose is not associated with any harm to the fetus or pregnant individual and may also decrease the risk for postpartum hemorrhage and the requirement for red blood cell transfusions.

Tier 2

A registry study of 336 pregnancies in untreated individuals with GD and 117 pregnancies in those treated with ERT, did not find significant differences in numbers of live births delivered at term, congenital anomalies, or spontaneous abortions between untreated and treated individuals. A study of 19 multiparous individuals with type 1 who had pregnancies before and after the institution of ERT found that risks of early postpartum hemorrhage and red blood cell transfusions were significantly lower when ERT was used during pregnancy, with odds ratios (95% confidence interval [CI]) of 0.13 (0.03-0.54) and 0.27 (0.08-0.94), respectively, compared to pregnancies without the use of ERT.

Tier 2

Surveillance

Following initial diagnosis, all individuals with GD (from asymptomatic to severely affected) should undergo the following assessments to establish the baseline disease characteristics, determine candidacy for treatment, and develop therapeutic goals and an individualized monitoring strategy. Individuals should continue to undergo comprehensive regular monitoring to assess the course of the disease and prevent development of serious, irreversible disease. The frequency of assessments varies by guideline and may be adjusted according to age, presence/absence of manifestations, and disease progression. The monitoring of asymptomatic individuals may be less frequent than treated individuals. Routine assessments should include:

• Comprehensive medical history of the individual and family, including a family pedigree

• Comprehensive physical examination (including growth velocity, height, and weight for children)

• Clinical evaluations: anemia, HSM, ocular, pulmonary, cardiac, and skeletal pathology. Routine evaluations for ocular apraxia may help to distinguish between type 1 and type 3 GD

• Imaging: Ideally, magnetic resonance imaging (MRI) for bone disease/abnormalities, organ volume, and lymphatic involvement, and dual-energy x-ray absorptiometry for bone density. Ultrasound exams are acceptable for monitoring organomegaly in asymptomatic children only until clinical deterioration makes ERT an option

• Biochemical markers: glucocerebrosidase, angiotensin-converting enzyme, tartrate-resistant acid phosphate, and chitotriosidase

• Laboratory evaluations: general hematology (including red blood cell and iron metabolism studies) and coagulation screens (not required for asymptomatic patients); liver and kidney function tests; thyroid/parathyroid panel; calcium and vitamin D levels; inflammation, HIV, and hepatitis; immunoglobulin profile; and baseline for antibodies to ERT

• Neurological evaluations:

-Neuronopathic GD: Cognitive function, neurological history including history of convulsions, cranial nerve assessment, motor assessment (e.g., ocular movement, neuro-ophthalmological investigations), neurological tests (e.g., electroencephalography, audiometry, brain stem auditory evoked potential), brain imaging, and neuropsychometry testing.

-Non-neuronopathic GD: Signs of Parkinsonian tremor

• Quality of life questionnaire.

Tier 2

In addition to the evaluations above, infants should be monitored at least quarterly to assess the development of additional manifestations that may require intervention. In children it is also important to evaluate development, social functioning, and school performance.

Tier 2

Circumstances to Avoid

Splenectomy should be avoided, particularly in children, and should only be considered in exceptional and emergency situations.

Tier 2

Individuals with certain CYP2D6 metabolizer genotypes under consideration for or actively undergoing SRT with eliglustat treatment must avoid certain CYP2D6 and CYP3A4 inhibitors that are either contraindicated or not recommended for concomitant use.

Tier 2

Individuals should avoid eliglustat during pregnancy and should consult a GD specialist if they become pregnant while taking the drug.

Tier 2

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in individuals with moderate to severe thrombocytopenia

Tier 4

Nature of Intervention

Nature of Intervention

Surveillance is frequent, extensive, and involves multiple providers, which could be burdensome. Surveillance imaging with MRI in young children usually requires sedation and some modalities should not be used routinely due to risk of radiation exposure.

Context: Adult Pediatric

ERT has demonstrated an excellent safety profile in individuals with GD and is generally well-tolerated, but administration poses unique age-related challenges in children. Administration is by intravenous infusion every 2 weeks with an infusion time of 1-2 hours. Initially, infusions must be given in the hospital, but treatment (for adult patients only) in the home after 6–12 months has become an option in some countries and can increase compliance and improve quality of life. Adverse reactions occur in less than 15% of individuals, are generally mild to moderate, are manageable, and do not prevent ongoing treatment. Up to 15% of individuals develop antibodies to imiglucerase, potentially reducing efficacy, and increasing the risk of hypersensitivity to the product, often causing adverse infusion reactions. Significant events that result in the discontinuation of treatment (e.g., anaphylaxis) are rare.

Context: Adult Pediatric

SRT with eliglustat is taken orally once or twice daily. However, strict adherence to daily treatment must be emphasized by the treating physician. Clinical trials reported the following most common adverse events for those taking eliglustat: joint stiffness/pain (17-45%), headache (13-40%), nasopharyngitis (13-15%), and nausea/diarrhea/back pain (10-12% each). Most of these events were mild, were documented only occasionally in most individuals, and often diminished with time. Serious adverse events were rare

Context: Adult Pediatric

Chance to Escape Clinical Detection

A group of experts reported that their combined experience of 362 individuals with GD revealed that misdiagnoses led to complications such as avascular necrosis, osteopenia, liver disease, bleeding complications, inappropriate procedures such as splenectomy and liver biopsy, and unnecessary chronic corticosteroid therapy.

Context: Adult Pediatric

Tier 3

Symptoms of GD are not easily recognized, and individuals frequently experience diagnostic delays. One study reported that because of diagnostic delays, individuals suffered from irreversible, disabling, and potentially life-threatening complications. Almost 25% of individuals with type 1 GD do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. The rarity of the disease and nonspecific and heterogeneous nature of GD symptoms may impede consideration of this disease as a differential diagnosis in a diagnostic work up.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			GBA			608013	0018150	0011945, 0009265, 0009266, 0009268, 0009267
GBA			231005	0018150	0009268, 0009266, 0009267, 0011945, 0009265
GBA			231000	0018150	0009267, 0009265, 0009266, 0011945, 0009268
GBA			230800	0018150	0009265, 0009267, 0011945, 0009268, 0009266
GBA			230900	0018150	0009266, 0009265, 0009267, 0011945, 0009268

References List

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