Beaulieu-Boycott-Innes Syndrome

A number sign (#) is used with this entry because of evidence that Beaulieu-Boycott-Innes syndrome (BBIS) is caused by homozygous or compound heterozygous mutation in the THOC6 gene (615403) on chromosome 16p13.

Description

Beaulieu-Boycott-Innes syndrome (BBIS) is an autosomal recessive neurodevelopmental disorder characterized by delayed development, moderate to severe intellectual disability, and dysmorphic facial features. Other developmental anomalies, such as cardiac and renal defects, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis, may also be present (summary by Beaulieu et al., 2013 and Amos et al., 2017).

Clinical Features

Boycott et al. (2010) described 2 pairs of sisters from 2 consanguineous Canadian Dariusleut Hutterite families with a distant common ancestor. The patients showed developmental delay with head circumference in the 2nd centile and distinctive facial features, including tall forehead, high anterior hairline, deep-set eyes with short and upslanted palpebral fissures, long nose, low-hanging columella, and thick vermilion of the upper and lower lip. The patients also had relatively mild renal malformations, including horseshoe kidney with right duplex collection system, unilateral kidney agenesis, and recurrent urinary tract infections. The sisters in 1 pair also had cardiac defects, with patent ductus arteriosus and perimembranous ventricular septal defect with left-to-right shunt in 1 sister and muscular ventricular septal defect that closed without intervention in the other; the sisters in the other pair also had gynecologic involvement, with premature ovarian failure in 1 sister and endometriosis in the other. All 4 patients had dental caries, and 2 sisters had dental malocclusion; 1 patient had mild velopharyngeal insufficiency. Boycott et al. (2010) noted that a specific cognitive profile appeared to be a feature of this syndrome: the 3 adult patients could read at grade level 4 but demonstrated extreme weakness in mathematics and tasks involving spatial reasoning.

Anazi et al. (2016) described a 4-year-old Saudi boy, born to first cousins once removed, with BBIS. The boy had an imperforate anus, undescended testes, atrial septal defect, ventricular septal defect, patent ductus arteriosus, height and weight more than 2 standard deviations below the mean, and normal head circumference (10th centile). Other features included broad forehead, bilateral epicanthus, low-hanging columella, thin lower lip with infralabial groove, pointed chin, mild camptodactyly, and overriding toes. His development was delayed: he sat at 1 year, walked at 2 years, and had no discernible words when evaluated at age 3 years.

Amos et al. (2017) described 3 unrelated patients from France, Iran, and the United States with BBIS. All 3 had microcephaly and intellectual disability; 2 had cardiac anomalies, 2 had hearing loss, and 2 had dental anomalies. Two had corpus callosum dysgenesis or dysplasia. On review of the clinical presentation of all reported patients, Amos et al. (2017) noted a relatively nonspecific phenotype that included moderate to severe intellectual disability, mild microcephaly to borderline-normal head circumference, and non-life-threatening congenital malformations including septal defects of the heart, structural renal defects, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis. Craniofacial features shared among patients included a tall forehead, short upslanting palpebral fissures, deep-set eyes, long nose, long hanging columella, retrognathia, and dental anomalies.

Inheritance

The transmission pattern in the family with moderate intellectual disability reported by Boycott et al. (2010) was consistent with autosomal recessive inheritance.

Mapping

In 2 related consanguineous Dariusleut Hutterite families segregating autosomal recessive microcephaly, developmental delay, and distinctive facial features, Boycott et al. (2010) used an identity-by-descent approach and SNP microarray analysis followed by haplotype analysis and identified a 5.1-Mb minimal homozygous region on chromosome 16p13.3 that was shared between all 4 patients and none of the unaffected sibs. Expression microarray analysis identified 7 genes that were downregulated compared to an unaffected sib, but sequencing revealed no mutations. Coding regions and intron/exon boundaries of an additional 8 genes were sequenced, but no mutations were found.

Molecular Genetics

In 2 sets of sisters from related Dariusleut Hutterite families with BBIS, Beaulieu et al. (2013) identified a homozygous missense mutation in the THOC6 gene (G46R; 615403.0001). The mutation, which was found by Sanger sequencing followed by exome sequencing, segregated with the disorder in the family and was not found in the NHLBI Exome Variant Server and dbSNP databases, in 435 control exomes, or in 150 controls from the general population. The variant was seen in heterozygous state in 3% of 92 Dariusleut controls and in 2% of 120 Lehrerleut controls. It was not present in 500 Schmeideleut controls. In vitro functional expression studies showed that the mutation caused abnormal intracellular localization; knockdown of THOC6 in HeLa cells caused increased apoptosis. In situ hybridization showed that the gene is highly expressed in the midbrain and eyes of developing zebrafish. No THOC6 mutations were found in 140 female patients with intellectual disability and microcephaly.

Using whole-exome sequencing, Anazi et al. (2016) identified a homozygous nonsense mutation in the THOC6 gene (R87X; 615403.0002) in a Saudi boy with BBIS. The mutation, which was confirmed by Sanger sequencing, was present in heterozygosity in his unaffected, consanguineous parents.

In 3 unrelated patients from France, Iran, and the U.S., Amos et al. (2017) identified homozygous or compound heterozygous mutations in the THOC6 gene (615403.0002-615403.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.