1. Disease characteristics
1.1 Name of the disease (synonyms)
Deficiency of UDP-galactose:O-beta-d-xylosylprotein 4-d-galactosyltransferase, deficiency of xylosylprotein 4-beta-galactosyltransferase, polypeptide 7, deficiency of galactosyltransferase I, B4GALT7 deficiency, B4GALT7-CDG, progeroid form of Ehlers–Danlos syndrome, type 1, Ehlers–Danlos syndrome with short stature and limb anomalies, Larsen of Reunion Island syndrome.
1.2 OMIM# of the disease
1.3 Name of the analysed gene or DNA/chromosome segments
1.4 OMIM# of the gene(s)
1.5 Mutational spectrum
Seven variants have been reported: six missense variants and one variant with a loss of function frameshift duplication (www.lovd.nl/B4GALT7). The c.808C>T (p.(Arg270Cys)) variant is the most prevalent one. Six variants have occurred within the region that codes for the catalytic protein domain. The standard reference sequence indicating reported variants (ENSG00000027847) and a reference for exon numbering (ENST00000029410) can be found at http://www.ensembl.org.
1.6 Analytical methods
Sanger sequencing of the eight coding exons and flanking intronic sequences of the B4GALT7 gene (NCBI reference sequence: NM_007255.2).
1.7 Analytical validation
Sanger sequencing identifies variants in >99% of patients. Deep intronic variants, large deletions and duplications would not be detected using this approach. Novel variants with uncertain effect on function are of course possible.
1.8 Estimated frequency of the disease
(Incidence at birth (‘birth prevalence’) or population prevalence)
If known to be variable between ethnic groups, please report):
1.9 Diagnostic setting
Comment: Deficiency of galactosyltransferase I is an autosomal recessive disorder of O-glycosylation, first reported in 1990.1 It is a proteoglycan defect, more specifically in the glycosaminoglycan biosynthesis. Glycosaminoglycans are attached to the serine residue of a core protein via a tetrasaccharide linkage (consisting of one xylose, two galactoses and one glucuronic acid residue). Other disorders of this ‘linkeropathy’ group are: XYLT1-CDG, XYLT2-CDG, B3GALT6-CDG and B3GAT3-CDG. These diseases belong to the congenital disorders of glycosylation (CDG), a large group of genetic defects in protein and lipid glycosylation. Most CDG are multisystem disorders with prominent neurological involvement. Nearly 100 CDG have been described. Subtype identification is challenging owing to the large clinical and genetic heterogeneity. There are protein glycosylation defects in N- and O-glycosylation. Most N-glycosylation disorders are recognized by serum transferrin isoelectrofocusing, whereas mucin-type O-glycosylation defects are diagnosed by apo C-III isoelectrofocusing.
All or the majority of reported patients with B4GALT7-CDG showed facial dysmorphism (including triangular face, sparse scalp hair, low-set ears, widely spaced eyes, narrow mouth and abnormal dentition), mild to severe intellectual/developmental disability, short stature, hypermobility, hypotonia, hyperelastic skin, limb bowing, pes planus, advanced bone age, radio-ulnar synostosis, and radial head and phalangeal dislocation. Less frequent findings comprised delayed/abnormal wound healing, wide forehead, flat face, proptosis, blue sclerae, glaucoma, bifid uvula, cleft palate, long slender fingers and toes, syndactyly and osteopenia. The large majority of the reported patients (22) are living on Reunion Island (in the ethnic group called ‘white creoles’). These Reunion Island patients lack osteopenia and recurrent fractures. They all carry the same homozygous c.808C>T (p.(Arg270Cys)) variant (founder effect). Current screening tests for defects in O-glycosylation (mainly apo C-III isoelectrofocusing) show normal results. The diagnosis of B4GALT7-CDG is based on the clinical acumen of the physician and confirmed by mutation analysis of B4GALT7. The identification of the pathogenic variant will permit heterozygote detection in the family and prenatal diagnosis.
2. Test characteristics
2.1 Analytical sensitivity
(proportion of positive tests if the genotype is present)
Not applicable as there is no test available.
2.2 Analytical specificity
(proportion of negative tests if the genotype is not present)
2.3 Clinical sensitivity
(proportion of positive tests if the disease is present)
The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.
2.4 Clinical specificity
(proportion of negative tests if the disease is not present)
The clinical specificity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.
2.5 Positive clinical predictive value
(life-time risk of developing the disease if the test is positive)
2.6 Negative clinical predictive value
(probability of not developing the disease if the test is negative)
Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.
Index case in that family had been tested:
Index case in that family had not been tested:
3. Clinical Utility
3.1 (Differential) diagnostics: The tested person is clinically affected
(To be answered if in 1.9 ‘A’ was marked).
3.1.1 Can a diagnosis be made other than through a genetic test?
3.1.2 Describe the burden of alternative diagnostic methods to the patient
3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?
3.1.4 Will disease management be influenced by the result of a genetic test?
3.2 Predictive Setting: The tested person is clinically unaffected but carries an increased risk based on family history
(To be answered if in 1.9 ‘B’ was marked).
3.2.1 Will the result of a genetic test influence lifestyle and prevention?
3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?
3.3 Genetic risk assessment in family members of a diseased person
(To be answered if in 1.9 ‘C’ was marked).
3.3.1 Does the result of a genetic test resolve the genetic situation in that family?
Usually yes, by testing the potential heterozygous persons (carriers) in the family.
3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?
3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?
3.4 Prenatal diagnosis
(To be answered if in 1.9 ‘D’ was marked).
3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?
Yes. Prenatal diagnosis should be performed by molecular analysis.
4. If applicable, further consequences of testing
Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe).
Knowledge of the diagnosis will stop unnecessary further investigations, and will help the parents in the process of accepting the disease although no curative treatment is available.
Quentin E, Gladen A, Rodén L, Kresse H : A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: galactosyltransferase I deficiency in fibroblasts from a patient with a progeroid syndrome. Proc Natl Acad Sci USA 1990; 87: 1342–1346.
Faiyaz-Ul-Haque M, Zaidi SHE, Al-Ali M et al: A novel missense mutation in the galactosyltransferase-I (B4GALT7 gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type. Am J Med Genet 2004; 128A: 39–45.
Guo MH, Stoler J, Lui J et al: Redefining the progeroid form of Ehlers-Danlos syndrome: report of the fourth patient with B4GALT7 deficiency and review of the literature. Am J Med Genet 2013; 161A: 2519–2527.
Cartault F, Munier P, Jacquemont ML et al: Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome. Eur J Hum Genet 2015; 23: 49–53.
Salter CG, Davies JH, Moon RJ et al: Further defining the phenotypic spectrum of B4GALT7 mutations. Am J Med Genet 2016; 170A: 1556–1563.
This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of health care’), a Coordination Action under FP7 (Grant Agreement Number 261469) and the European Society of Human Genetics.
The authors declare no conflict of interest.
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Cite this article
Jaeken, J., Lefeber, D. & Matthijs, G. Clinical utility gene card for: B4GALT7-defective congenital disorder of glycosylation. Eur J Hum Genet 25, 271 (2017). https://doi.org/10.1038/ejhg.2016.151