Chromosome 17p13.1 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene syndrome caused by deletion of chromosome 17p13.1

Clinical Features

Krepischi-Santos et al. (2009) reported a girl from the United Kingdom and 3 Brazilian boys, who were each found to have a microdeletion within or spanning chromosome 17p13.1. All presented with severe to profound mental retardation, absent or very poor speech, small head, and poor growth. Other features were variable among the patients, which the authors noted might be partially explained by different genes involved in their specific deletions.

Schwarzbraun et al. (2009) studied a 7-year-old girl with mental retardation, who spoke only a few words and had an ataxic gait. Evaluation at 5 months of age had revealed psychomotor retardation with generalized muscle hypotonia. Dysmorphic features included a broad and low-set nasal bridge, short philtrum, and bifid uvula; the child could not establish visual contact. Brain MRI revealed an enlarged fourth ventricle and hypoplasia of the cerebellar vermis and corpus callosum, consistent with incomplete Dandy-Walker malformation (see 220200) or Dandy-Walker variant. Short episodes of myoclonic seizures occurred within the first year of life.

Schluth-Bolard et al. (2010) reported a 10-year-old boy who had mild global developmental delay and facial dysmorphism, including frontal bossing, hypertelorism, flat nasal root, midface hypoplasia, small nose, short philtrum, thin upper lip, up-turned corners of the mouth, small chin, and low-set ears. Physical examination also showed finger joint hyperlaxity, pes planus, astigmatism, hypermetropia, and conductive hearing loss secondary to chronic otitis media. Skin examination showed achromic patches following the lines of Blaschko on the right upper quarter of the thorax, the right arm, and forearm suggesting a diagnosis of hypomelanosis of Ito (300337). Brain MRI, cardiac echocardiography, abdominal ultrasound, auditory brainstem evoked responses, and funduscopy were normal.

Shlien et al. (2010) studied 4 patients in whom array CGH or MLPA had identified microdeletions at chromosome 17p13.1, encompassing the TP53 locus. All 4 patients had a noncancer phenotype comprising a spectrum of congenital anomalies, including pervasive developmental delay and mental retardation, speech difficulties, hypotonia, facial dysmorphisms, and hand and foot abnormalities. Facial dysmorphisms included high forehead, highly arched eyebrows, downslanting palpebral fissures, epicanthal folds, prominent nasal bridge, upturned nasal tip, thin lips, downturned corners of mouth, high-arched palate, and a small and recessed chin. Patients were hypotonic and displayed ligamentous laxity, with contractures at the elbows and knees; deep tendon reflexes were brisk and ankle clonus was present. Hands and feet were short, and proximally placed thumbs and/or broad great toes were present in some patients.

Molecular Genetics

In 4 patients with syndromic mental retardation, Krepischi-Santos et al. (2009) identified microdeletions of chromosome 17p13.3-p13.1, ranging in size from 287 kb to 4.4 Mb, each with unique breakpoints. An overlapping segment of approximately 180 kb of chromosome 17p13.1 encompassed 18 genes, including TP53 (191170) and several other tumor suppressor genes. No tumors had been reported yet in any of the 4 patients, but Krepischi-Santos et al. (2009) noted that this was not unexpected given their relatively young ages, ranging from 5 years to 18.5 years, and suggested that long-term oncologic surveillance would be warranted in these patients.

By array CGH analysis followed by sequencing analysis in a 7-year-old girl with mental retardation, facial dysmorphism, impaired vision, seizures, and Dandy-Walker variant, Schwarzbraun et al. (2009) identified a 774-kb de novo deletion in chromosome 17p13.1 that encompassed 47 genes. The authors noted that several of the deleted genes could presumably be related to some of the patient's phenotypic features: loss of the KCNAB3 potassium channel gene (604111), for example, would be likely to be involved in the occurrence of the patient's seizures. In addition, the GUCY2D gene (600179), mutation in which can cause cone-rod dystrophy-6 (CORD6; 601777), was disrupted from the cis-regulatory elements by the breakpoint; ophthalmoscopic examination confirmed the presence of CORD in the patient, a diagnosis that explained the patient's severely impaired vision. Although the TP53 gene was within the deleted region in this patient, she did not fulfill the criteria for Li-Fraumeni (151623) or Li-Fraumeni-like syndrome, as she had no tumor and a negative family history.

In a 10-year-old boy with developmental delay, facial dysmorphism, and joint laxity, Schluth-Bolard et al. (2010) performed array CGH and identified a de novo 400-kb microdeletion on chromosome 17p13.1 involving TP53 and 25 other genes. The authors reviewed 7 previously reported patients with 17p13.1 microdeletions, including those of Krepischi-Santos et al. (2009) and Schwarzbraun et al. (2009), and stated that although all had mental retardation of variable degrees, their dysmorphic features were not specific and no recognizable syndrome emerged from comparison of the patients. Schluth-Bolard et al. (2010) noted that all the deletions were of different sizes and did not share common breakpoints, thus making it unlikely that a nonallelic homologous recombination (NAHR) mechanism generated these deletions.

Shlien et al. (2010) screened 4,524 patients with diverse clinical phenotypes for DNA dosage changes via array CGH or MLPA and identified 8 probands with a microdeletion of chromosome 17p13.1, encompassing the TP53 locus. In 4 of the patients, deletions were limited to the TP53 gene, and all 4 had childhood cancer and pedigrees consistent with the Li-Fraumeni syndrome but no neurocognitive symptoms. The remaining 4 patients, who had a noncancer phenotype comprising developmental delay, hypotonia, facial dysmorphisms, and hand and foot anomalies, had microdeletions of varying sizes at chromosome 17p13.1, encompassing the entire TP53 gene and 26 to 85 other fully deleted genes. Shlien et al. (2010) analyzed the expression of 24 genes within a common deleted region and found that the most significantly changed gene at 17p13.1, TRAPPC1 (610969), was also the most significantly changed gene genomewide, with more than 2-fold lower expression in patients compared to controls. Shlien et al. (2010) highlighted 3 other deleted genes in this region: MPDU1 (604041), mutations in which cause the congenital disorder of glycosylation CDG1F (609180), involving severe mental and psychomotor retardation; FXR2 (605339), a homolog of the fragile X mental retardation gene, FMRP (309550); and EFNB3 (602297), known to be important in the development of normal locomotor behavior. To determine whether the deletions unmasked a recessive mutation, Shlien et al. (2010) sequenced these 4 genes, but did not find additional mutations. In addition, Shlien et al. (2010) compared mRNA expression patterns in the 4 patients with a noncancer neurocognitive phenotype to those of the 4 patients with childhood cancer who had microdeletions within the TP53 gene, and found that mRNA expression levels of TP53 and TP53-dependent genes were altered in the patients with partial, but not complete, deletions, which was consistent with mutant TP53-initiated tumorigenesis in the former group but not in the latter. Analysis of the breakpoints of the 17p13.1 microdeletions demonstrated that most arose by Alu-mediated NAHR.