Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature.
Beaulieu-Boycott-Innes syndrome
THOC6 gene
prenatal phenotype
Journal
Birth defects research
ISSN: 2472-1727
Titre abrégé: Birth Defects Res
Pays: United States
ID NLM: 101701004
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
17
03
2022
received:
28
08
2021
accepted:
22
03
2022
pubmed:
16
4
2022
medline:
3
6
2022
entrez:
15
4
2022
Statut:
ppublish
Résumé
The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss-of-function variants of the THOC6 gene were identified in the Beaulieu-Boycott-Innes syndrome (BBIS- OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano-genital and renal congenital malformations. In the present study, we report on a new family with two affected sibs. The 6-year-old female had severe intellectual disability with autistic features, feeding difficulties, growth delay, facial dysmorphic, and congenital malformations (hand, skeletal and cardiac anomalies). The male fetus presented antenatally with a cystic hygroma associated with severe aortic and left ventricular hypoplasia. Autopsy, after termination of pregnancy at 15 weeks of gestation, showed facial dysmorphic, short right thumb and hypospadias. Exome sequencing detected in both sibs compound heterozygous variants of the THOC6 gene (NM_024339.3, GRCh37): the already reported c.[298T>A;700G>T;824G>A] haplotype and a novel variant c.977T>G, p.(Val326Gly). We made a review of the literature of 17 BBIS reported patients including our two siblings. Severe to moderate ID and congenital malformations were constant. Prenatal and postnatal failure to thrive were frequent. Brain MRI were not specific. Prenatal findings were reported in 40% of cases but we described the first case of cystic hygroma. The present study reports extends the prenatal delineation of the phenotypic features observed in association with the presence of THOC6 variants. In addition, it underscores the intrafamilial phenotypic variability observed in BBIS.
Sections du résumé
BACKGROUND
The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss-of-function variants of the THOC6 gene were identified in the Beaulieu-Boycott-Innes syndrome (BBIS- OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano-genital and renal congenital malformations.
METHODS
In the present study, we report on a new family with two affected sibs. The 6-year-old female had severe intellectual disability with autistic features, feeding difficulties, growth delay, facial dysmorphic, and congenital malformations (hand, skeletal and cardiac anomalies). The male fetus presented antenatally with a cystic hygroma associated with severe aortic and left ventricular hypoplasia. Autopsy, after termination of pregnancy at 15 weeks of gestation, showed facial dysmorphic, short right thumb and hypospadias.
RESULTS
Exome sequencing detected in both sibs compound heterozygous variants of the THOC6 gene (NM_024339.3, GRCh37): the already reported c.[298T>A;700G>T;824G>A] haplotype and a novel variant c.977T>G, p.(Val326Gly).
DISCUSSION
We made a review of the literature of 17 BBIS reported patients including our two siblings. Severe to moderate ID and congenital malformations were constant. Prenatal and postnatal failure to thrive were frequent. Brain MRI were not specific. Prenatal findings were reported in 40% of cases but we described the first case of cystic hygroma. The present study reports extends the prenatal delineation of the phenotypic features observed in association with the presence of THOC6 variants. In addition, it underscores the intrafamilial phenotypic variability observed in BBIS.
Substances chimiques
RNA-Binding Proteins
0
THOC6 protein, human
0
Types de publication
Case Reports
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
499-504Informations de copyright
© 2022 Wiley Periodicals LLC.
Références
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Amos, J. S., Huang, L., Thevenon, J., Kariminedjad, A., Beaulieu, C. L., Masurel-Paulet, A., … Care4Rare Canada Consortium. (2017). Autosomal recessive mutations in THOC6 cause intellectual disability: Syndrome delineation requiring forward and reverse phenotyping. Clinical Genetics, 91(1), 92-99. https://doi.org/10.1111/cge.12793
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Casey, J., Jenkinson, A., Magee, A., Ennis, S., Monavari, A., Green, A., … Hughes, J. (2016). Beaulieu-Boycott-Innes syndrome: An intellectual disability syndrome with characteristic facies. Clinical Dysmorphology, 25(4), 146-151. https://doi.org/10.1097/MCD.0000000000000134
Gupta, N., Yadav, S., Gurramkonda, V. B., Vl, R., Sg, T., & Kabra, M. (2020). First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India. European Journal of Medical Genetics, 63(3), 103742. https://doi.org/10.1016/j.ejmg.2019.103742
Mattioli, F., Isidor, B., Abdul-Rahman, O., Gunter, A., Huang, L., Kumar, R., … Piton, A. (2019). Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Human Molecular Genetics, 28(6), 952-960. https://doi.org/10.1093/hmg/ddy391
Zhang, Q., Chen, S., Qin, Z., Zheng, H., & Fan, X. (2020). The first reported case of Beaulieu-Boycott-Innes syndrome caused by two novel mutations in THOC6 gene in a Chinese infant. Medicine, 99(15), e19751. https://doi.org/10.1097/MD.0000000000019751