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Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report.
BMC Med Genet. 2020 01 30; 21(1):18.BM

Abstract

BACKGROUND

Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance.

CASE PRESENTATION

We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03.

CONCLUSION

This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.

Authors+Show Affiliations

Medical Genetics Department, Vinmec Times City International Hospital-Times City, HaNoi, Vietnam.Fetal Medicine Department, Vinmec Times City International Hospital-Times City, HaNoi, Vietnam.Diagnostic Imaging Department, Vinmec Times City International Hospital-Times City, HaNoi, Vietnam.Center for Molecular Medicine, University of Medicine and Pharmacy, Ho Chi Minh city, Vietnam.Medical Genetics Department, Vinmec Times City International Hospital-Times City, HaNoi, Vietnam.Medical Genetics Department, Vinmec Times City International Hospital-Times City, HaNoi, Vietnam.Medical Genetics Department, Vinmec Times City International Hospital-Times City, HaNoi, Vietnam. minhtuannia82@yahoo.it.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

32000717

Citation

Bui, Thi Phuong Hoa, et al. "Novel Compound Heterozygous TMEM67 Variants in a Vietnamese Family With Joubert Syndrome: a Case Report." BMC Medical Genetics, vol. 21, no. 1, 2020, p. 18.
Bui TPH, Nguyen NT, Ngo VD, et al. Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report. BMC Med Genet. 2020;21(1):18.
Bui, T. P. H., Nguyen, N. T., Ngo, V. D., Nguyen, H. N., Ly, T. T. H., Do, H. D., & Huynh, M. T. (2020). Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report. BMC Medical Genetics, 21(1), 18. https://doi.org/10.1186/s12881-020-0962-0
Bui TPH, et al. Novel Compound Heterozygous TMEM67 Variants in a Vietnamese Family With Joubert Syndrome: a Case Report. BMC Med Genet. 2020 01 30;21(1):18. PubMed PMID: 32000717.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report. AU - Bui,Thi Phuong Hoa, AU - Nguyen,Ngoc Tu, AU - Ngo,Van Doan, AU - Nguyen,Hoai-Nghia, AU - Ly,Thi Thanh Ha, AU - Do,Huy Duong, AU - Huynh,Minh-Tuan, Y1 - 2020/01/30/ PY - 2019/11/01/received PY - 2020/01/24/accepted PY - 2020/2/1/entrez PY - 2020/2/1/pubmed PY - 2020/3/4/medline KW - Joubert syndrome KW - Molar tooth sign KW - Novel TMEM67 splice-site variant KW - Whole exome sequencing SP - 18 EP - 18 JF - BMC medical genetics JO - BMC Med. Genet. VL - 21 IS - 1 N2 - BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders. SN - 1471-2350 UR - https://www.unboundmedicine.com/medline/citation/32000717/Novel_compound_heterozygous_TMEM67_variants_in_a_Vietnamese_family_with_Joubert_syndrome:_a_case_report_ L2 - https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-0962-0 DB - PRIME DP - Unbound Medicine ER -