Chromosome 6q24-Q25 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.

Clinical Features

Pirola et al. (1998) described a 9-month-old girl who had hydrocephalus noted on fetal ultrasonography and was born with marked muscular hypotonia and dysmorphic features including dolichocephaly, high-arched and occult submucous cleft palate, low-set ears, relatively long distal phalanges of fingers, and an anteriorly placed anus. CT scan of the head revealed agenesis of the corpus callosum (see ACC, 217990) and dilation of both lateral ventricles; MRI revealed the presence of Probst bundles.

Bisgaard et al. (2006) reported a 6.5-year-old girl with short stature that was not explained by hormone analyses and stimulation tests and a 3-year delay in bone age. Failure to thrive had followed repair of a ventricular septal defect (VSD) in infancy. She had slightly delayed psychomotor development and facial dysmorphism that included almond-shaped eyes, short nose, full cheeks, smooth philtrum, thin upper lip, low-set ears, and a protruding, dysplastic left ear.

Caselli et al. (2007) described an 8-year-old girl who had neonatal persistence of fetal circulation and respiratory distress, in whom tricuspid insufficiency, right ventricular dilation, patent ductus arteriosus, atrial septal defect (ASD), and increased pulmonary resistance were detected. She had delayed psychomotor development with mild mental retardation. Examination at the age of 8 years, 2 months revealed short stature, mild facial asymmetry, medial flare eyebrows, short palpebral fissures, dysmorphic helix of the right ear, cup-shaped left ear, anteverted nares, thin upper lip, long and smooth philtrum, and high-arched palate. She had small hands and small, flat feet with increased distance between the first and second toes. Echocardiogram showed an atrial septal defect with minimal shunt; MRI of brain, EEG, auditory and visual evoked responses, and abdominal ultrasound were all normal. Caselli et al. (2007) noted that the phenotype of the patient described by Bisgaard et al. (2006) was 'remarkably similar' to this patient.

Nowaczyk et al. (2008) studied 3 unrelated patients with de novo paternal interstitial deletions of 6q24.3. Although the 3 patients had deletions of different sizes with different breakpoints, 2 of the patients shared a 2.5-Mb region of overlap and strikingly similar facial features, including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They both had congenital heart defects, with dysplastic tricuspid and pulmonary valves with mild regurgitation, mitral valve prolapse, and premature ventricular contractions in 1 patient and left axial displacement of the heart chambers and a large patent foramen ovale with a secundum atrial septal defect in the other patient. Additional features in common included redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all 3 patients was a less than 1-Mb deletion interval; all 3 patients had a history of intrauterine growth retardation (IUGR) and postnatal short stature without overt radiologic skeletal anomalies. The third patient, who had only IUGR and short stature, had previously been studied by Kumar et al. (1999).

Nagamani et al. (2009) reported 4 patients with interstitial deletions involving chromosome 6q25, all of whom had microcephaly, developmental delay, dysmorphic features, and hearing loss; 2 patients also had agenesis of the corpus callosum.

Cytogenetics

In a 9-month-old girl with agenesis of the corpus callosum with Probst bundles, born of healthy parents, Pirola et al. (1998) detected a de novo unbalanced karyotype with an approximately 8-cM interstitial deletion on chromosome 6q25 between D6S1496 and D6S437; the final karyotype was 46,XX,del(6)(q25.1q25.3) and the deletion was determined to have arisen on the paternal chromosome 6.

Kumar et al. (1999) studied a 3.3-year-old girl with intrauterine growth retardation and short stature who was otherwise developmentally normal, who had a karyotype of 46,XX,del(6)(q23.3q24.2). FISH analysis showed that the approximately 4- to 5-Mb deletion breakpoints lay between markers WI-5023 and D6S1024. Microsatellite analysis demonstrated that the de novo deletion was paternal in origin.

In a 6.5-year-old girl with VSD, short stature, facial dysmorphism, and psychomotor delay, Bisgaard et al. (2006) detected an apparently balanced paracentric inversion of chromosome 4 inherited from the father (46,XX,inv(4)(q11.2q13)pat); metaphase CGH revealed a de novo interstitial deletion of chromosome 6q25, with a real-time PCR estimate of 6.88 to 7.21 Mb.

In an 8-year-old girl with ASD, short stature, facial dysmorphism, and psychomotor delay, Caselli et al. (2007) performed array CGH and detected an approximately 2.6-Mb chromosome 6 interstitial deletion (46,XX,del(6)(q24.3q25.1)), with the proximal breakpoint located between 148.70 Mb and 148.78 Mb and the distal breakpoint between 151.28 Mb and 151.35 Mb. Noting the phenotypic similarities between this patient and the girl previously reported by Bisgaard et al. (2006) with a 7-Mb overlapping deletion, Caselli et al. (2007) concluded that this may represent a specific new 6q25 interstitial deletion syndrome. Caselli et al. (2007) stated that the overlapping critical deleted region contained 22 genes.

Osoegawa et al. (2008) analyzed DNA samples from individuals born with cleft lip and cleft palate and identified a nonsyndromic patient with unilateral right cleft lip and cleft palate who had a de novo 3.2-Mb deletion at chromosome 6q25.1-q25.2. The proximal breakpoint of the deletion was within a 43-kb region between markers rs17855719 and rs851997, and the distal breakpoint was localized to a 120-kb region between rs1106753 and rs2273898. The microdeletion was determined to have arisen on the paternal chromosome 6. Osoegawa et al. (2008) noted that there were 11 genes in the deleted region.

In 3 patients with intrauterine growth retardation and short stature who had de novo paternally derived interstitial deletions of chromosome 6q, Nowaczyk et al. (2008) performed FISH analysis and narrowed the region of common deletion to a 1-Mb interval between 145.9 and 146.9 Mb from the 6p telomere at 6q24.3, a segment containing 5 described genes, none of which had known function involving pre- or postnatal growth. Two of the patients, who exhibited the additional findings of early developmental delay, congenital heart defects, and a facial appearance that was strikingly similar, had deletions that extended more distally than that of the third patient, who had previously been studied by Kumar et al. (1999).

In 4 patients with microcephaly, developmental delay, dysmorphic features, and hearing loss, 2 of whom also had agenesis of the corpus callosum, Nagamani et al. (2009) performed array CGH followed by high-resolution nucleotide array and detected deletions ranging from 3.77 to 13.81 Mb on chromosome 6q. The commonly deleted 3.52-Mb interval on 6q25.2-q25.3 contains 12 protein-coding genes, all but 1 of which are expressed in the brain. Nagamani et al. (2009) compared the deleted regions in the 2 patients with ACC to those of previously reported patients with ACC and 6q deletions, including the patient described by Pirola et al. (1998), and delimited a critical 3.3-Mb interval for ACC on 6q25.2-q25.3.

Thienpont et al. (2010) reviewed the genotype and phenotype data from 12 patients with a chromosomal deletion on 6q, including patients previously reported by Pirola et al. (1998), Kumar et al. (1999), Bisgaard et al. (2006), Caselli et al. (2007), Nowaczyk et al. (2008), and Nagamani et al. (2009), and delineated an 850-kb critical region for congenital heart disease on chromosome 6q25.1. Bioinformatics prioritization of the 5 candidate genes at this locus identified the TAB2 gene (605101) as the top-ranking candidate for a role in congenital heart disease.

Molecular Genetics

Thienpont et al. (2010) analyzed the TAB2 gene in 402 patients with cardiac outflow tract defects and identified heterozygosity for missense mutations (605101.0001 and 605101.0002) in 2 patients with multiple types of congenital heart disease (614980); neither mutation was found in 658 ethnically matched control chromosomes. In addition, in a family with congenital aortic stenosis and cardiac arrhythmias segregating with a balanced t(2;6)(q21;q25) translocation, previously reported by Bache et al. (2006), Thienpont et al. (2010) performed FISH analysis that localized the 2q21 breakpoint to a 14.2-kb region disrupting the POTEE gene (608914) and the 6q25 breakpoint to a 17-kb region within the first intron, first exon, or promoter region of TAB2. Noting that POTEE is not expressed in the human heart and is variable in copy number in the normal human population, Thienpont et al. (2010) concluded that perturbations and mutations of TAB2 cause congenital heart defects.