Chromosome 17q11.2 Deletion Syndrome, 1.4-Mb

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome. The deletion region of chromosome 17q11.2 includes the NF1 gene (613113), which is mutant in neurofibromatosis type I (162200).

Description

Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).

Clinical Features

Kayes et al. (1994) reported 5 NF1 patients with deletions of chromosome 17q11.2 including the NF1 gene. All had mild facial dysmorphism, mental retardation, and/or learning disabilities. Five patients were remarkable for the large number of neurofibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or development. All had plexiform neurofibromas. Four had hypertelorism, 4 had ptosis, and all had micrognathia.

Using FISH with intragenic probes, Wu et al. (1995) looked for deletions in 13 unrelated individuals with NF1. Among 6 with severe manifestations, 4 were found to have deletions of the entire NF1 gene. All 4 had severe developmental delay, minor and major anomalies (including 1 with bilateral iris colobomas), and multiple cutaneous neurofibromas or plexiform neurofibromas which were present before age 5 years.

Riva et al. (1996) characterized a 12-year-old male patient with sporadic NF1, dysmorphism, mental retardation, and skeletal anomalies associated with a cytogenetically visible deletion at 17q11.2. Analysis of microsatellite markers demonstrated that the patient was hemizygous, due to loss of the paternal allele, at several sites within the NF1 gene and at an extragenic marker distal to the 3-prime end of NF1. The 9-cM deletion in the interval between D17S841 and D17S250 was in agreement with that originally detected cytogenetically. The karyotypes of the parents were normal. The patient had no neurofibromas; the authors attributed this fact to his genetic background, i.e., to the influence of modifying genes.

Upadhyaya et al. (1996) claimed to have provided the first physical cytogenetic deletion involving the NF1 gene in a patient with sporadic neurofibromatosis, dysmorphic features, and marked developmental delay. Combined evidence of molecular and cytogenetic techniques predicted that the deletion was approximately 7 Mb.

Wu et al. (1997) described a father and son with NF1 due to deletion of the entire NF1 gene detected by FISH. Both had severe NF1, including a large number of cutaneous neurofibromas, facial anomalies, large hands, feet, and head, and developmental impairment. Only the 15-year-old son had seizures and plexiform neurofibromas.

Cnossen et al. (1997) studied DNA from 84 unrelated patients with NF1, unselected for clinical features or severity, screening for deletion with intragenic polymorphic repeat markers and Southern analysis with cDNA probes. Deletion of the entire gene was detected in 5 patients from 4 unrelated families. Their phenotype resembled that of 5 previously reported patients with deletions, including intellectual impairment and dysmorphic features, but they could not confirm the existence of an excessive number of dermal neurofibromas. The authors commented on features of postnatal overgrowth suggesting Weaver syndrome (277590) and manifestations somewhat like Noonan syndrome (NS1; 163950). Slight micrognathia and extreme overbite of the maxilla were noted in individual cases.

Using a novel multitrack screening strategy, Upadhyaya et al. (1998) studied 67 NF1 families (54 2-generation, 13 3-generation) with a de novo mutation in the germline of the first generation; 2 extragenic and 11 intragenic markers were employed. The pathologic lesion was identified in 31 cases. Loss of heterozygosity in the affected individual revealed a gross gene deletion in 15 of the 2-generation families; in 12 (80%) of them, the deletion was maternally derived. Eleven patients with a gross deletion exhibited developmental delay, 10 had dysmorphic features, and 6 manifested a learning disability. No gross deletion was apparent in any of the 13 3-generation families, suggesting that such lesions are subject to more intense selection. In these 13 families, the new mutation was of paternal origin in 11 and the underlying mutation event could be characterized in 3 of them.

Rasmussen et al. (1998) studied 67 patients with NF1 and their parents. Five patients showed loss of heterozygosity, suggesting NF1 gene deletion. These patients did not have severe NF1 manifestations, mental retardation, or dysmorphic features. All 5 deletions were de novo and occurred on the maternal chromosome. Two patients showed partial loss of heterozygosity, consistent with somatic mosaicism for NF1 deletion.

Streubel et al. (1999) described what they considered to be the third case of NF1 due to mosaicism for a gross deletion in 17q11.2 covering the entire NF1 gene. The deletion was suspected in Giemsa banded chromosomes and was confirmed by fluorescence in situ hybridization using probes spanning the entire 350-kb genomic DNA of the NF1 gene. The deletion was present in 33% of peripheral blood lymphocytes and 58% of fibroblasts. The clinical manifestations in their 6-year-old male patient were especially severe and extended beyond the typical features of NF1. The patient also displayed facial anomalies, severe and early-onset psychomotor retardation, seizures, spasticity, and microcephaly. These features differed from other large-deletion NF1 patients, even nonmosaic cases. Streubel et al. (1999) suggested that the complex phenotype could be explained by the involvement of coding sequences flanking the NF1 gene, thus supporting the existence of a contiguous gene syndrome in 17q11.2. The other cases of somatic mosaicism for a deletion of the entire NF1 gene as identified by FISH were reported by Tonsgard et al. (1997) and Wu et al. (1997).

By combining clinical and genetic evidence from 92 patients with the NF1 microdeletion, Venturin et al. (2004) reviewed specific clinical signs of the NF1 microdeletion syndrome. They found that the most common extra-NF1 clinical signs in patients with the microdeletion were learning disability, cardiovascular malformations, and dysmorphism. They pictured 3 patients with NF1 microdeletion syndrome in whom hypertelorism was a conspicuous feature of the facial dysmorphism. From the gene content of the deleted region, Venturin et al. (2004) proposed that haploinsufficiency of the OMG (164345) and/or CDK5R1 (603460) genes may be implicated in learning disability. In relation to cardiovascular malformations, only JJAZ1 (SUZ12; 606245) and CENTA2 (ADAP2; 608635) were considered plausible candidate genes, by reason of being significantly expressed in the heart.

Mautner et al. (2010) reported 29 patients, including a mother and daughter, with the 17q11.2 deletion syndrome whose deletions were accurately characterized using FISH, PCR, and microsatellite analysis. All of the deletions were consistent with 1.4-Mb type 1 deletions encompassing 14 genes. Clinical features included facial dysmorphism (90%), tall stature (46%), large hands and feet (46%), scoliosis (43%), joint hyperflexibility (72%), delayed cognitive development and/or learning disabilities (93%), and mental retardation (38%). These features were more common than observed in the general NF1 population. Compared to the NF1 population, deletion patients also had significantly increased frequencies of plexiform neurofibromas (76%), subcutaneous neurofibromas (76%), spinal neurofibromas (64%) and malignant peripheral nerve sheath tumors (21%). Of the adults, 50% had a very high burden of cutaneous neurofibromas (greater than 1,000). Novel clinical features associated with type 1 NF1 deletions included pes cavus (17%), bone cysts (50%), attention deficits (73%), muscular hypotonia (45%), and speech difficulties (48%). Mautner et al. (2010) concluded that the phenotype associated with NF1 deletions is more severe than that observed in patients with typical neurofibromatosis type 1.

NF1 Microduplication Syndrome

Grisart et al. (2008) reported a large family segregating a microduplication of the NF1 microdeletion syndrome region. Two adult brothers had developmental delay and mild mental retardation associated with early onset of baldness around 14 to 15 years of age, mild facial dysmorphism with sparse eyelashes and eyebrows, long midface, malar hypoplasia, nasal deviation, bifid nose tip, flared nares, thin upper lip, dental enamel hypoplasia, and large testes. Family history included a similarly affected father with 3 mentally retarded half sisters and a mentally retarded half brother. The deceased grandmother was also reportedly affected. Microarray CGH, FISH analysis, and multiple ligation-dependent probe amplification (MLPA) detected a 1.5- to 1.6-Mb duplication on chromosome 17q11 corresponding perfectly to the NF1 microdeletion syndrome region. This duplication was found in all affected individuals studied, as well as in 2 unaffected family members, indicating reduced penetrance. Grisart et al. (2008) noted that the same mechanism, nonallelic homologous recombination, underlies both microdeletion and microduplication.

Molecular Genetics

About 5% of all patients with neurofibromatosis type I (NF1) have large deletions in 17q11.2 that include both the NF1 gene and its flanking regions. There are 3 main types of chromosome 17q11.2 deletions. The most common deletion is type 1, a 1.4-Mb deletion generated by nonallelic homologous recombination (NAHR) between segmental duplications (NF1-REP A and NF1-REP C) leading to the loss of 14 functional genes. These breakpoint regions are also known as the paralogous recombination sites 1 and 2 (PRS1 and PRS2, respectively). Type 1 is the most common deletion, accounting for 60 to 70% of large NF1 deletions. The less common type 2 deletion spans 1.2 Mb and is also generated by NAHR with breakpoints located within the SUZ12 gene (606245) and its pseudogene SUZ12P, resulting in the loss of 13 genes. Type 2 deletions account for 10 to 20% of large deletions in this region and are frequently associated with somatic mosaicism. The third type of deletions are atypical deletions of variable size, with nonrecurrent breakpoints (summary by Mautner et al., 2010).

Kayes et al. (1994) reported 5 patients with a heterozygous deletion of more than 700 kb on chromosome 17. Minimally, each of the deletions involved the entire 350-kb NF1 gene, the 3 genes (EVI2A, 158380; EVI2B, 158381; and OMG, 164345) contained within an NF1 intron, and considerable flanking DNA. In 4 of the patients, the deletion mapped to the same interval; the deletion in the fifth patient was larger, extending farther in both directions. The remaining NF1 allele appeared to be producing functional neurofibromin. The data provided compelling evidence that NF1 results from haploid insufficiency of neurofibromin. Of the 3 documented de novo deletion cases, 2 involved the paternal NF1 allele and 1 the maternal allele. The findings suggested that clinical variability in NF1 may be influenced by genes either contiguous to or contained within the NF1 gene.

Dorschner et al. (2000) constructed a 3.5-Mb BAC/PAC/YAC contig at 17q11.2. Analysis of somatic cell hybrids from microdeletion patients showed that 14 of 17 cases had deletions of 1.5 Mb. Deletions encompassed the entire 350 kb NF1 gene, 3 additional genes, 1 pseudogene, and 16 ESTs. In these cases, both proximal and distal breakpoints mapped at chromosomal regions of high identity, which the authors termed NF1-REPs. These REPs, or clusters of paralogous loci, are 15 to 100 kb and harbor at least 4 ESTs and an SH3GL pseudogene. The remaining 3 patients had at least 1 breakpoint outside an NF1-REP element; 1 had a smaller deletion, thereby narrowing the critical region harboring the putative locus that exacerbates neurofibroma development to 1 Mb. These data showed that the likely mechanism of NF1 microdeletion is homologous recombination between NF1-REPs on sister chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified that results in loss of a tumor suppressor gene. Therefore, in addition to the germline rearrangements that Dorschner et al. (2000) identified, NF1-REP-mediated somatic recombination may be an important mechanism for the loss of heterozygosity at the NF1 locus in tumors of NF1 patients.

Lopez Correa et al. (2000) analyzed a set of polymorphic dinucleotide-repeat markers flanking the microdeletion on chromosome 17 in a group of 7 unrelated families with a de novo NF1 microdeletion. Six of 7 microdeletions were of maternal origin. The breakpoints of the microdeletions of maternal origin were localized in NF1-REPs. The single deletion of paternal origin was shorter, and no crossover occurred on the paternal chromosome 17 during transmission. Five of the 6 cases of maternal origin were informative, and all 5 showed a crossover (between the flanking markers) after maternal transmission. The observed crossovers flanking the NF1 region suggested to the authors that these NF1 microdeletions resulted from an unequal crossover in maternal meiosis I, mediated by a misalignment of the flanking NF1-REPs.

Shen et al. (2000) found that the SLC6A4 (182138) and CPD (603102) genes were deleted in 1 of 17 NF1 patients carrying submicroscopic NF1 contiguous gene deletions.

Lopez-Correa et al. (2001) mapped and sequenced the microdeletion breakpoints in 54 NF1 patients. In 25 such patients, recombination events occurred in a discrete 2-kb recombination hotspot within each of the flanking NF1-REPs. Two recombination events were accompanied by apparent gene conversion. A search for recombination-prone motifs revealed a chi-like sequence.

Jenne et al. (2001) used molecular techniques to characterize the breakpoints and deleted genes in 8 patients with NF1 and 17q11.2 microdeletion syndrome. The interstitial 17q11.2 microdeletion arose from unequal crossover between 2 highly homologous 60-kb duplicons separated by approximately 1.5 Mb. The authors stated that 13 genes had been located in the deleted region.

Kehrer-Sawatzki et al. (2004) identified a high frequency of mosaicism among patients with NF1 caused by microdeletions resulting from somatic recombination of the JJAZ1 gene (SUZ12; 606245). Two types of deletions were observed. The classic 1.4-Mb deletion (type 1) was found in some patients. These type 1 deletions encompass 14 genes and have breakpoints in the NF1 low-copy repeats (LCRs). The 1.2-Mb NF1 deletion (type 2) affected 13 genes and was mediated by recombination between the JJAZ1 gene and its pseudogene. The JJAZ1 gene, which was completely deleted in patients with type 1 NF1 microdeletions and disrupted in type 2 deletions, is highly expressed in brain structures associated with learning and memory. Thus, its haploinsufficiency might contribute to mental impairment in patients with constitutional NF1 microdeletions. Conspicuously, 7 of the 8 mosaic deletions were of type 2, whereas only 1 was a classic type 1 deletion. Therefore, the JJAZ1 gene is a preferred target of strand exchange during mitotic nonallelic homologous recombination. Although type 1 NF1 microdeletions occur by interchromosomal recombination during meiosis, the findings of Kehrer-Sawatzki et al. (2004) implied that type 2 deletions are mediated by intrachromosomal recombination during mitosis.

Gervasini et al. (2005) reported an NF1 patient with a 1.5-Mb deletion involving the NF1 gene. High-resolution FISH showed that the centromeric breakpoint was within the SSH2 gene (606779), and the telomeric breakpoint was within IVS23A of the NF1 gene; both breakpoints occurred in Alu sequences. Gervasini et al. (2005) noted that most Alu-mediated deletions are much smaller (up to 200 kb). The patient had a relatively mild phenotype with borderline cognitive deficits and seizures, but no dysmorphism or cardiac anomalies, suggesting that genes mapping downstream from NF1 may account for those manifestations.

The breakpoints of the common 1.4-Mb (type 1) 17q11.2 deletion are located within low-copy repeats (NF1-REPs) and cluster within a 3.4-kb hotspot of nonallelic homologous recombination (NAHR). Steinmann et al. (2007) presented a comprehensive breakpoint analysis of the 1.2-Mb type 2 deletions, characterized by breakpoints located within the SUZ12 gene (606245) and its pseudogene. Breakpoint analysis of 13 independent type 2 deletions revealed no obvious hotspots of NAHR. However, an overrepresentation of polypyrimidine/polypurine tracts and triplex-forming sequences was noted in the breakpoint regions that could have facilitated NAHR. All 13 type 2 deletions identified were characterized by somatic mosaicism, which indicates a positional preference for mitotic NAHR with the NF1 gene region. Whereas interchromosomal meiotic NAHR occurs between the NF1-REPs giving rise to type 1 deletions, NAHR during mitosis appears to occur intrachromosomally between the SUZ12 gene and its pseudogene, thereby generating type 2 deletions. Additionally, 12 of the 13 mosaic type 2 deletions were found in females. The marked female preponderance among mosaic type 2 deletions contrasts with the equal sex distribution noted for type 1 and/or atypical NF1 deletions. Although an influence of chromatin structure was strongly suspected, no sex-specific differences in the methylation pattern exhibited by the SUZ12 gene were apparent that could explain the higher rate of mitotic recombination in females.

Type 2 NF1 deletions are believed to have an early postzygotic mitotic origin. Using microsatellite analysis, Roehl et al. (2010) analyzed 14 additional type 2 NF1 deletions and found that most type 2 NF1 deletions originated via intrachromosomal NAHR between SUZ12 and its highly homologous pseudogene. Combined with the findings of Steinmann et al. (2007), the results indicated that 16 of 18 type 2 NF1 deletions occurred postzygotically via the same method. Two unrelated patients, 1 with a severe phenotype, apparently had germline type 2 NF1 deletions.

Associations Pending Confirmation

By mutation screening of 12 of the 14 genes deleted in the type 1 chromosome 17q11 microdeletion, Douglas et al. (2007) identified heterozygous mutations in the RNF135 gene (611358.0001-611358.0004) in 4 of 245 unrelated individuals with an overgrowth syndrome characterized by increased postnatal height and weight, macrocephaly, variable learning disability, and dysmorphic facial features. One additional individual had a microdeletion of RNF135 and 4 other genes, but not NF1. Although none had clinical features of NF1, the facial features were similar to the NF1 deletion syndrome, including broad forehead, downslanting palpebral fissures, broad nasal tip, long philtrum, and thin upper lip. Variable features in 1 or 2 patients included deafness, optic nerve hypoplasia, advanced bone age, ataxia, autistic features, and pulmonary stenosis. Douglas et al. (2007) concluded that haploinsufficiency of RNF135 contributes to the overgrowth and facial dysmorphism that is often present in individuals with NF1 microdeletions, as well as learning disabilities and other congenital anomalies. Functional studies were not performed.

Wright et al. (2019) used data from 379,768 UK Biobank participants of European ancestry to access the pathogenicity and penetrance of putatively clinically important rare variants. Two variants in the RNF135 gene, Q243X (611358.0001) and a 1-bp insertion, had no statistically significant association with years of education, fluid intelligence, BMI, or height. The Q243X variant was found at a minor allele frequency (MAF) of 0.00215, and the 1-bp insertion at a MAF of 0.05265. Wright et al. (2019) argued that, based on the lack of association with any clinically relevant traits, the probability of 0 of the gene's being loss-of-function (LOF)-intolerant (based on the presence in ExAC of LOF variants in the gene; Lek et al., 2016), the age of the report of Douglas et al. (2007), and the lack of enrichment of de novo mutations in the Deciphering Developmental Disorders Study (2017), RNF135 haploinsufficiency is not a cause of impaired intellectual development.

Animal Model

Venturin et al. (2014) found that morpholino-mediated knockdown of adap2 in zebrafish embryos resulted in variable circulatory defects at 2 days postfertilization, including total loss of circulation, accumulation of blood cells in the trunk and/or tail, and blood stases in the head. Circulatory defects in adap2 morphants appeared to be caused by abnormal heart development and function, including lack of leftward cardiac jogging, abnormal heart looping (including presence of a completely linear heart tube), reduced ventricle size, and abnormal atrioventricular valve formation. Venturin et al. (2014) hypothesized that occurrence of cardiovascular malformations in NF1 microdeletion patients is due to ADAP2 haploinsufficiency.