Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant ... Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 17q12 deletion was identified in 18 cases and no controls for a p value of 0.00015 and a frequency of 1 in 875 cases. - Renal Cysts and Diabetes Syndrome Bellanne-Chantelot et al. (2005) studied 40 unrelated patients with a clinical phenotype consistent with maturity-onset diabetes of the young type 5 (MODY5; 137920), in which patients present with renal cysts and diabetes, and found molecular alterations of the TCF2 gene (HNF1B; 189907) in 28 (70%). Point mutations were identified in 18 patients and 10 had gross genomic rearrangements, which in 9 patients involved a deletion of at least 1.2 Mb, delimited by the TCF2 and TRIP3 (604500) genes and encompassing 7 other genes and 2 predicted proteins. One patient had a single-exon deletion of exon 5. The authors observed a similar phenotype in patients with point mutations and patients with large deletions. Various genital tract abnormalities were also found in 80% of the patients with TCF2 alterations who were tested. Bellanne-Chantelot et al. (2005) concluded that large genomic rearrangements of TCF2 can cause MODY5 and that whole-gene deletion is the most frequent molecular alteration in MODY5 patients. Using array-based comparative genomic hybridization, Mefford et al. (2007) assessed chromosomal regions predisposed to recurrent rearrangements in 155 autopsy samples from fetuses with well-defined developmental pathologies. They found that 6% of fetal material showed evidence of microdeletion or microduplication, including 3 independent events that likely resulted from unequal crossing-over between segmental duplications. A 1.8-Mb deletion encompassing the TCF2 gene on chromosome 17q12 was identified in a fetus with multicystic dysplastic kidneys. Oligonucleotide array analysis of deletion breakpoints in 8 patients known to have deletions encompassing the TCF2 gene, including 5 patients with pediatric renal disease without diabetes and 3 patients with MODY5, revealed that 4 of the 5 pediatric patients and all 3 of the MODY5 patients had deletions 'nearly identical' to that of the fetal case, with breakpoints in all cases mapping to flanking segmental-duplication blocks. The deletion was not found in a control group of 960 unrelated Caucasian individuals. Mefford et al. (2007) concluded that 17q12 deletion is a recurrent genomic disorder with breakpoints in flanking segmental duplications that results in renal disease and diabetes. The authors also identified the reciprocal duplication (see 614526). Nagamani et al. (2010) studied 9 patients with genomic rearrangements in chromosome 17q12, including 4 patients with a deletion and 5 with a duplication. The patients with a deletion, who were all in the first 2 decades of life, had presented with renal disease, including cystic renal disease, multicystic renal dysplasia, and renal agenesis; 2 had preserved renal function, 1 had a nonfunctioning right kidney, and 1 had end-stage renal disease treated with a renal transplant. All 4 patients had short stature; 3 had features suggestive of central nervous system involvement, ranging from speech delay to moderately severe mental retardation, and 2 of those patients had complex partial seizures. Only 1 of the 4 patients had diabetes, which was post-renal transplant drug-induced diabetes. The deletions in all 4 patients encompassed a minimum of 1.06 Mb, extending from the LHX1 gene (601999) to LOC28400, and a maximum of 2.46 Mb, extending from the CCL3L3 gene (609468) to the SNIP gene (610786). - Mullerian Aplasia/Dysgenesis and Associated Features Cheroki et al. (2008) performed genomewide array CGH screening in 14 women exhibiting mullerian aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome, MRKH; 277000) and associated features, and identified a 1.8-Mb deletion on chromosome 17q12 in a 45-year-old woman with severe learning disabilities, seizures, mild facial dysmorphism, horizontal nystagmus, complete absence of uterus/vagina, long and thin arms, legs, hands, and feet, and onychodystrophy. She had normal ovaries and secondary sexual characteristics. Cheroki et al. (2008) stated that the deletion encompassed the LHX1 (601999) and TCF2 genes, and noted that although deletion of TCF2 has been shown to cause the renal cysts and diabetes syndrome (MODY5), this patient did not have diabetes or any renal malformations. Bernardini et al. (2009) reported 2 female patients with MRKH syndrome who had identical de novo 1.5-Mb deletions at chromosome 17q12. One was a 20-year-old woman with mildly dysmorphic facial features who presented for evaluation of primary amenorrhea and had complete absence of the uterus and vagina; pelvic MRI showed bilaterally normal ovaries and kidneys. The other patient was a 15-year-old girl who had bilateral renal cysts noted on fetal ultrasound and at 5 years of age had small, multicystic kidneys on ultrasound. At 12 years of age, menarche was complicated by hematocolpos due to agenesis of the upper and middle thirds of the vagina, which was surgically corrected. At laparoscopy, mullerian malformations were seen, including right unicornuate uterus, noncavitating rudimentary left horn, and right hematosalpinx. Growth and psychomotor development were normal in both patients, and both had normal blood glucose levels. The deletions encompassed 16 genes, including the 2 candidate genes, LHX1 and TCF2. Bernardini et al. (2009) performed a focused chromosome 17 array CGH analysis in 20 consecutive MRKH patients but detected no abnormalities; direct sequencing of the candidate genes TCF2 and LHX1 likewise revealed no pathogenic mutations. - Autism Spectrum Disorder and Schizophrenia Loirat et al. (2010) reported 3 unrelated boys with heterozygous de novo deletions in chromosome 17q12, cystic or hyperechogenic kidneys, and autism (see 209850). The boys were part of a larger cohort consisting of 86 children with cystic kidneys and known HNF1B molecular anomalies, of which 33 (39%) were point mutations and 53 (61%) were whole-gene deletions. The 3 boys had hyperechogenicity and/or cysts of the renal cortex noted on prenatal ultrasonography; 1 of them had moderate renal failure and mild cholestasis at last follow-up at age 9 years. All 3 developed signs consistent with the diagnostic criteria for autism between the ages of 6 months and 2 years, displaying developmental delay and social interaction impairments, verbal and nonverbal communication deficits, and stereotyped behaviors. Genetic screening for known causes of autism was negative. Their 17q12 deletions ranged from 1.5 to 1.8 Mb, with proximal and distal breakpoints located within segmental duplications, similar to those reported in patients with renal disease/diabetes only. The deletions included the LHX1, HNF1B, and 19 other genes; sequencing of the LHX1 gene in the 3 boys and 32 control patients with autism revealed no mutations. Loirat et al. (2010) concluded that autism might be an additional manifestation associated with HNF1B deletion. Moreno-De-Luca et al. (2010) performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders and detected a recurrent 1.4-Mb deletion at chromosome 17q12 in 18 of 15,749 patients, including several with autism spectrum disorder (see 209850); the deletion was not found in 4,519 controls. In 9 patients who were available for evaluation, shared phenotypic features were observed, including macrocephaly; characteristic facial features consisting of epicanthal folds, downslanting palpebral fissures, arched and high eyebrows, slightly depressed nasal bridge, and malar flattening; genitourinary tract anomalies, including prenatal echogenic renal calyces and hydronephrosis, unilateral and bilateral cystic kidneys, urethral stenosis, and uterus didelphis; and neurocognitive impairment, primarily affecting speech. Autism or autistic features were present in all 6 male patients. Only the oldest patient, a 37-year-old woman, had diabetes. In addition, recurrent infections of the ear, upper respiratory system, and urinary tract, scoliosis, and hypermetropia were each observed in more than 2 cases. In a large follow-up sample, the same deletion was identified in 2 of 1,182 patients with autism spectrum disorder and/or neurocognitive impairment, and in 4 of 6,340 schizophrenia (see 181500) patients, but was not found in 47,929 controls (corrected p = 7.37 x 10 (-5)). Moreno-De-Luca et al. (2010) concluded that deletion 17q12 is a recurrent, pathogenic CNV that confers a high risk for autism spectrum disorder and schizophrenia, and that 1 or more of the 15 genes in the deleted interval is dosage-sensitive and essential for normal brain development and function.