Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.
THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment.
Medical Genetics Section, SUNY Upstate Medical University, Syracuse, NY, USA.
J S
JS
Amos
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
L
L
Huang
Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|EA4271-Génétique des Anomalies du développement, Université de Bourgogne, Dijon, France.
J
0000-0001-9271-3961
J
Thevenon
Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
A
A
Kariminedjad
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
C L
CL
Beaulieu
Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|EA4271-Génétique des Anomalies du développement, Université de Bourgogne, Dijon, France.
A
A
Masurel-Paulet
Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.|Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
H
H
Najmabadi
Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.|Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Z
Z
Fattahi
Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.|Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
M
M
Beheshtian
Pediatric Neurology Research Center, SBMU, Tehran, Iran.
S H
SH
Tonekaboni
Ambry Genetics Corporation, Aliso Viejo, CA, USA.
S
S
Tang
Ambry Genetics Corporation, Aliso Viejo, CA, USA.
K L
KL
Helbig
Ambry Genetics Corporation, Aliso Viejo, CA, USA.
W
W
Alcaraz
Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|EA4271-Génétique des Anomalies du développement, Université de Bourgogne, Dijon, France.
J-B
JB
Rivière
Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|EA4271-Génétique des Anomalies du développement, Université de Bourgogne, Dijon, France.
L
L
Faivre
Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.
A M
AM
Innes
Medical Genetics Section, SUNY Upstate Medical University, Syracuse, NY, USA.
R R
RR
Lebel
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
K M
KM
Boycott
D000293:Adolescent; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D000072417:Protein Domains; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D012720:Severity of Illness Index; D013577:Syndrome
D016601:RNA-Binding Proteins; C000620275:THOC6 protein, human
Beaulieu-Boycott-Innes syndrome; THO complex; THOC6; congenital malformations; dysmorphism; exome sequencing; intellectual disability