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.

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).

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.

Accogli et al. (2018) described an Italian girl with BBIS who was born to nonconsanguinous parents. Born at 39 weeks' gestation, she was small for gestational age and required mechanical ventilation for a few days. On physical exam, she had a short soft palate, anterior displacement of the anus, and a trigger thumb of the right hand. She also had right hip dislocation, left ectopic dysplastic kidney, and bilateral optic hypoplasia. On brain MRI she had hydrocephalus due to aqueductal stenosis and cerebellar hypoplasia with severe vermian dysgenesis. Spinal MRI showed multiple segmentation defects of the cervical vertebrae, 11 thoracic vertebrae, and sacralization of L5. When seen at age 16 years, she had short stature and hypergonadotropic hypogonadism. She had dysmorphic facial features consistent with BBIS. The authors proposed that the severe phenotype seen in this patient broadened the phenotype to include hydrocephalus with aqueductal stenosis, cerebellar hypoplasia, and multiple vertebral anomalies.

Mattioli et al. (2019) reported 2 unrelated patients originating from northern Europe with BBIS. The first patient, a boy, was born at 35 weeks' gestation with intrauterine growth restriction, a micropenis, and a short corpus callosum. He had neonatal hypotonia and feeding difficulties and developed severe cognitive impairment. He had upper limb stereotypies and autistic behaviors. He had dysmorphic features consistent with other patients with BBIS. The second patient, a girl, was born at 34 weeks' gestation due to concerns for fetal movements. At birth, she had cleft palate, micrognathia, choanal atresia, a patent ductus arteriosus requiring ligation, and an atrial septal defect. She had hydrocephalus requiring a ventriculoperitoneal shunt. She later had severe developmental delays. In addition to dysmorphic features consistent with BBIS, she had other complications including alternating exotropia, nystagmus, hyperopia, bilateral sensorineural hearing loss, seizures, chronic lung disease, and pulmonary hypertension.

Beaulieu et al. (2013) demonstrated autosomal recessive inheritance of BBIS in Dariusleut Hutterite families.

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.

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 Schmiedeleut 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.

In an Italian girl with BBIS, Accogli et al. (2018) identified compound heterozygosity for 2 loss-of-function mutations in the THOC6 gene (615403.0007-615403.0008). The mutations were found by trio exome sequencing and confirmed by Sanger sequence. Each parent was heterozygous for one of the mutations.

Using trio exome sequencing in 2 unrelated patients with BBIS, Mattioli et al. (2019) identified homozygosity for a rare haplotype in the THOC6 gene that includes 3 amino acid changes (W100R, V234L, G275D; 615403.0009) due to maternal uniparental disomy of chromosome 16 in a male patient, and in a female patient, compound heterozygosity for the same haplotype inherited from her mother and a previously reported missense variant (G19E; 615403.0005) inherited from her father.