Chromosome 14q11-Q22 Deletion Syndrome

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

Clinical Features

Grammatico et al. (1994) reported a boy with severe psychomotor retardation and dysmorphic features associated with a small de novo interstitial deletion of chromosome 14q11.2-q13 identified by karyotype analysis. In the first months of life, he was noted to have microcephaly with plagiocephaly, spastic tetraparesis, left hip subluxation, and poor growth. Dysmorphic features included upslanting palpebral fissures, flat nasal bridge with enlarged nares, and poorly folded auricular lobes. He also had cryptorchidism and low implanted thumbs. Neurologic examination at age 3 years showed autistic-like behavior, inability to follow with the eyes, vertical nystagmus, and inability to sit or walk unsupported.

Shapira et al. (1994) reported 2 unrelated girls, of Hispanic and Vietnamese descent, respectively, with psychomotor delay and failure to thrive associated with de novo deletions of proximal 14q. Common features included microcephaly, poor growth, and hypoplasia of the corpus callosum. Both had dysmorphic features, which varied somewhat. The first girl had triangular face, high-arched palate, and prominent chin. Other features included generalized hypertonia, brisk tendon reflexes, poor head control, and inability to fix and follow visually. The second girl had plagiocephaly, open anterior fontanel, prominent forehead, asymmetric low-set, posteriorly-rotated ears, epicanthal folds, flat nasal bridge, small mouth, and micrognathia. She also had a patent foramen ovale, patent ductus arteriosus, and severe hypotonia. Cytogenetic analysis showed deletions of chromosome 14q11.2-q21.1 and 14q12-q22, respectively, which was confirmed by molecular analysis. Both were de novo and occurred on the paternal chromosome.

Govaerts et al. (1996) reported another patient with a de novo interstitial deletion at chromosome 14q11.2-q13. He had microcephaly, slightly protruding eyes with epicanthus, high narrow palate, short neck, and arthrogryposis. He had severe developmental delay and did not achieve eye contact. He also had unilateral renal cysts and diabetes insipidus. Death occurred at age 7 months from pneumonia. The deletion was found on the paternally derived chromosome.

Ramelli et al. (2000) reported a boy with severely delayed psychomotor development, microcephaly, spastic tetraparesis, esotropia, inability to follow with the eyes, broad nose, and coarse facial features. Brain MRI showed agenesis of the corpus callosum and abnormal myelination pattern. Cytogenetic analysis identified an interstitial deletion of chromosome 14q11.2-q13.1. The findings were similar to those in the patient reported by Grammatico et al. (1994).

Kamnasaran et al. (2001) reviewed the clinical features of 9 unrelated children with deletions or translocations involving the chromosome 14q11-q22 region, 5 of whom had been previously reported. Common features of 6 patients with deletions included microcephaly, hypotonia, poor growth, mental retardation with poor eye contact, and hypoplasia of the corpus callosum. Dysmorphic features, when reported, were mild and variable, including short nose, long philtrum, and flat nasal bridge.

Zahir et al. (2007) reported 3 unrelated children with a de novo interstitial deletion of chromosome 14q11.2. One was of English Canadian descent, 1 of Japanese descent, and 1 of English descent. All had hypotonia in infancy followed by developmental delay and cognitive impairment. Similar mild dysmorphic features included widely-spaced eyes, broad flat nasal bridge and short nose, a long philtrum, small mouth, prominent Cupid's bow of the upper lip, full lower lip, eyebrows with a triangular medial aspect and distal tapering, and an usual abnormality of helical root formation of the ear. One child had a ventricular septal defect and patent ductus arteriosus.

Torgyekes et al. (2011) reported 2 unrelated patients with deletion of proximal 14q13.1. Both children had severe developmental delay, failure to thrive, microcephaly, and distinctive facial features, including hypertelorism, epicanthal folds, sloping forehead, low-set ears, rounded eyebrows with triangular media aspect and outer tapering, depressed and broad nasal bridge, small mouth, long philtrum, and prominent Cupid's bow. Brain MRI of both children showed partial agenesis of the corpus callosum. One patient also had bilateral hypoplastic optic nerves causing blindness, mild hearing impairment, sinus arrhythmia, abnormal temperature regulation, frequent apneic episodes, myoclonic jerks, and opisthotonus. The second had a seizure disorder confirmed by EEG, sleep apnea, chronic interstitial lung disease, and several episodes of pneumonia and gastroenteritis.

Cytogenetics

By flow cytometry, followed by microsatellite mapping, Kamnasaran et al. (2001) defined the breakpoints of 9 unrelated children with deletions or translocations involving chromosome 14q11-q22, 5 of whom had been previously reported. In 5 of the 6 patients with deletions, including the 2 reported by Shapira et al. (1994), the deletion intervals ranged from 9 cM to over 27 cM, and there was no correlation between phenotypic severity and size of the deletion intervals. Kamnasaran et al. (2001) found that the remaining deletion case, reported by Grammatico et al. (1994), had a more proximal deletion at 14q with only minimal overlap with 3 of the other deletion patients and no overlap with the 2 patients reported by Shapira et al. (1994). The 3 patients had translocations and a very different phenotype. One was a man with a t(4;14)(q12;13) karyotype who had small phallus, undescended right testis, and mild mental impairment. He had a son with similar clinical findings who also carried the translocation. The other 2 unrelated individuals, with t(4;14)(q21;q13) and t(14;18)(q13q12), respectively, had no neurologic deficits, but only short stature and mesomelic bone dysplasia, respectively. Kamnasaran et al. (2001) suggested the PAX9 gene (167416) as a putative locus for mesomelic bone dysplasia in the patients with 14q translocation.

In 3 unrelated patients with delayed development and mild dysmorphic features, Zahir et al. (2007) identified 3 different de novo deletions of chromosome 14q11.2, ranging in size from 101 kb to 1.6 Mb, with a 35-kb overlapping region including the SUPT16H (605012) and CHD8 (610528) genes. Zahir et al. (2007) noted that the deleted region in their 3 patients did not overlap with the chromosome 14q11-q22 deletions that had been previously reported.

In a 5-year-old girl with infantile onset of intractable epileptic encephalopathy, severe psychomotor retardation, and hypotonia, but without dysmorphic features, Shimojima et al. (2009) identified a de novo heterozygous 2.2-Mb deletion of chromosome 14q13.1-q13.3. The deleted region encompassed 15 genes, but only the TULIP1 gene (RALGAPA1; 608884) was known to be predominantly expressed in the brain. Direct sequencing of the TULIP1 gene in 140 samples from patients with developmental delay and/or epilepsy identified 4 different heterozygous missense variants in 4 unrelated patients; however, all the variants were inherited from an unaffected parent. Functional studies of the variants were not performed, but decreased amounts of TULIP1 protein were found in the cells of the patient with the large deletion and in 1 of the 4 patients with a missense mutation. Morpholino knockdown of the tulip1 gene in zebrafish embryos resulted in delayed brain development.

In 2 unrelated patients with severe developmental delay and dysmorphic facial features, Torgyekes et al. (2011) identified 2 overlapping deletions of proximal 14q. One patient had a 6-Mb deletion of 14q12-q13.1, whereas the other had a balanced 3-way translocation, 46,XY,t(4;14;11)(q33;q12;q22.2), resulting in a 12-Mb deletion of 14q and no copy number aberrations involving the other 2 chromosomes. In a review of the literature of similar cases, Torgyekes et al. (2011) found that the deletion sizes ranged from 3.0 to 30.0 Mb with few common breakpoints and no smallest common region of deletion. The authors discussed the potential involvement of several candidate genes in the deleted regions, including FOXG1B (164874) and ARHGAP5 (602680).