Clinical characteristics.

The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., global developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural renal anomalies occur in 80% to 85% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: 10 to 50 years).

Diagnosis/testing.

The diagnosis is established in a proband by detection of the 1.4-megabase (Mb) heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods.

Management.

Treatment of manifestations: Treatment of renal anomalies, MODY5, and developmental brain disorders should follow standard practice.

Surveillance:

• Kidneys and urinary tract. In the absence of known structural abnormalities, renal ultrasound examination 12 months after establishing the diagnosis, then every 2-3 years in childhood/adolescence, then every 3-5 years in adulthood; presence of an abnormality may warrant more frequent monitoring. Annual monitoring of renal function in patients with abnormalities detected on renal ultrasound examination; more frequent monitoring may be advised in those taking potentially nephrotoxic medications and/or known to have impaired kidney function.
• MODY5. HgbA1C annually; self-monitoring by patients and their families for clinical signs and symptoms of diabetes mellitus.
• Psychomotor development. Routine monitoring through early childhood; full neuropsychological evaluation for children who experience difficulty with school.

Agents/circumstances to avoid: Because renal transplantation increases the risk for new-onset diabetes after transplantation (NODAT), an immunosuppressive regimen that avoids tacrolimus and reduces corticosteroid exposure may benefit those without preexisting diabetes mellitus.

Evaluation of relatives at risk: If one of the proband's parents has the 17q12 recurrent deletion, it is appropriate to test older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of renal structural or functional defects, MODY5, and developmental delays/intellectual disability.

Genetic counseling.

The 17q12 recurrent deletion is inherited in an autosomal dominant manner, with approximately 70% of deletions occurring de novo and approximately 30% inherited from a parent. If the 17q12 recurrent deletion identified in the proband is not found in one of the parents, the risk to sibs is presumed to be lower than 1% (but slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism for the deletion). Offspring of an individual with the 17q12 recurrent deletion have a 50% chance of inheriting the deletion. Prenatal testing or preimplantation genetic diagnosis using genomic testing that will detect the 17q12 recurrent deletion is possible.

Suggestive Findings

17q12 recurrent deletion syndrome should be suspected in individuals with any of the following suggestive clinical and laboratory findings:

Suggestive clinical findings

• Renal abnormalities:
  • Congenital abnormalities of the kidney and urinary tract (CAKUT), including the following: hyperechogenic kidneys on prenatal ultrasound examination, cystic dysplastic kidneys, poor cortico-medullary differentiation, renal dysplasia, renal hypoplasia, single kidney, horseshoe kidney, collecting system abnormalities
  • Tubulointerstitial disease, characterized by reduced urine concentrating ability, hyperuricemia, hypomagnesemia, hypokalemia with bland urinary sediment, absent-to-minimal albuminuria/proteinuria, and tubulointerstitial fibrosis on renal histology. In some cases, hypomagnesemia is the initial and predominant symptom of renal disease [van der Made et al 2015].
• Maturity-onset diabetes of the young (MODY), a type of monogenic diabetes resulting from beta-cell dysfunction
• Neurodevelopmental or neuropsychiatric disorders (e.g., global developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder)
• Müllerian aplasia/Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome in females
  Note: The combination of renal or urogenital anomalies with MODY has been referred to as renal cysts and diabetes (RCAD) syndrome.

Suggestive laboratory findings

• Deletion of HNF1B identified on gene-targeted deletion/duplication analysis (i.e., testing that detects deletion of HNF1B but cannot reliably detect the diagnostic recurrent 17q12 deletion), as virtually all whole-gene deletions have been found to be the 17q12 recurrent deletion [Laffargue et al 2015]

Note that identification of an intragenic HNF1B pathogenic variant on sequence analysis establishes the diagnosis of an HNF1B-related disorder (see Genetically Related Disorders) and excludes the diagnosis of the 17q12 recurrent deletion syndrome.

Establishing the Diagnosis

The diagnosis of the 17q12 recurrent deletion syndrome is established in a proband by detection of the 1.4-Mb heterozygous recurrent deletion at chromosome 17q12. Most individuals with the 17q12 recurrent deletion are identified by:

• Chromosomal microarray analysis (CMA) used in the evaluation of the cause of developmental delay, intellectual disability, or autism spectrum disorder;
  OR
• HNF1B deletion/duplication analysis or CMA performed in the context of evaluation of renal or urogenital anomalies, often with concurrent maturity-onset diabetes of the young (MODY5). Note: Virtually all whole-gene deletions of HNF1B identified by gene-targeted deletion/duplication analysis have been shown to include the entire recurrent deletion region [Laffargue et al 2015], which can be confirmed using CMA.

For this GeneReview, the minimum size for the 17q12 recurrent deletion is 1.4 Mb of unique DNA sequence at the approximate position of chr17: 34,815,072-36,192,492 in the reference genome (GRCh37/hg19). ISCN nomenclature for this deletion is: seq[GRCh37] del(17)(q12) chr17:g.34815072_36192492del.

Note: Since this deletion is recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with the syndrome; however, the reported size of the deletion may: (1) be larger if adjacent segmental duplications are included in the size and (2) vary based on the design of the microarray used to detect it.

For information on the 15 known genes the 17q12 region see Molecular Genetics.

Genomic testing (chromosomal microarray analysis [CMA] or comprehensive genomic sequencing) is used to diagnose the 17q12 recurrent deletion in a proband.

• Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays is recommended to detect the 17q12 recurrent deletion.
  Note: (1) The 17q12 recurrent deletion cannot be identified by routine analysis of G-banded chromosomes (karyotype) or other conventional cytogenetic banding techniques. (2) The ability to size the deletion depends on the type of microarray used and the density of probes in the 17q12 region. (3) Prior to 2007, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
• Comprehensive genomic sequencing: caveat. Comprehensive genomic sequencing (when available) including exome sequencing and genome sequencing may detect the 17q12 recurrent deletion only when the analysis includes CNV detection methods. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: renal abnormalities including congenital abnormalities of the kidney and urinary tract (CAKUT) and tubulointerstitial disease, maturity-onset diabetes of the young (MODY), and neurodevelopmental/neuropsychiatric disorders (e.g., global developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder).

To calculate the frequency rates for these features reported in 17q12 recurrent deletion syndrome, the authors reviewed phenotypic information for 164 individuals on whom sufficiently detailed phenotypic information was reported in 28 studies (Table 2) using the following criteria:

• Studies involving disease-specific cohorts were not included in the prevalence calculations of that particular phenotypic manifestation (e.g., renal anomalies) to minimize ascertainment bias.
• Individuals with HNF1B pathogenic sequence variants were not included; however, individuals with whole-gene HNF1B deletions were included, as virtually all whole-gene deletions have been found to be the 17q12 recurrent deletion [Laffargue et al 2015].

Intrafamilial Variability

While the recurrent 17q12 deletion most often occurs de novo, there have been several reports of familial inheritance [Mefford et al 2007, Moreno-De-Luca et al 2010, George et al 2012, Quintero-Rivera et al 2014]. Although the size of the deletion did not differ between parents and children in these reports, significant variability in clinical presentation included the following:

• In one family both father and child had renal cysts; however, only the proband exhibited duodenal atresia and a midline cystic lesion [Quintero-Rivera et al 2014].
• In one family both mother and child had multicystic kidneys, while neurodevelopmental and neuropsychiatric features differed significantly: the proband had autism spectrum disorder and significant global developmental delay, whereas his mother had bipolar disorder but no autistic features [Moreno-De-Luca et al 2010].
• In one family the mother had learning difficulties but no evidence of renal anomalies or diabetes mellitus, whereas one of her two children with the deletion had bilateral multicystic kidneys and the other had low average intellectual function, disruptive behavior, and ADHD, but no renal involvement [George et al 2012].

Penetrance

Penetrance of the 17q12 recurrent deletion is high, but expressivity is variable.

One study examining the prevalence of the recurrent 17q12 deletion among individuals with neurodevelopmental and neuropsychiatric disorders did not find any instances of 17q12 deletion among the roughly 48,000 controls [Moreno-De-Luca et al 2010]. In a different study, the 17q12 recurrent deletion was detected in about one in 14,500 presumably healthy individuals in the general population [Stefansson et al 2014]. The infrequent occurrence of the deletion in control populations is consistent with a high rate of penetrance.

Furthermore, some degree of renal impairment, including structural and functional anomalies, is present in more than 80% of reported individuals with the 17q12 recurrent deletion, providing further evidence for a high rate of penetrance with variable expressivity.

Nomenclature

In 1997, heterozygous pathogenic variants in HNF1B were described as a cause of MODY in one family [Horikawa et al 1997]; shortly thereafter the same family was found to have kidney involvement [Iwasaki et al 1998]. In 2001, the combination of congenital anomalies of the kidney and urinary tract and MODY5 became known as "renal cysts and diabetes (RCAD) syndrome" [Bingham et al 2001].

Prevalence

In a study of the homogeneous population of Iceland, the17q12 recurrent deletion was found in one in approximately 14,500 individuals [Stefansson et al 2014].

The prevalence of the17q12 recurrent deletion is higher among populations of individuals with certain specific clinical findings:

• Schizophrenia: About 1:1,500 [Grozeva et al 2012]
• Neurodevelopmental disorders: 1:875 [Moreno-De-Luca et al 2010].
• Cohorts with renal disease:
  • Mean of 2.8% (29/1,027) in six studies selected for more severe CAKUT (e.g., renal hypodysplasia or single functioning kidney) and, in some instances, for family history or the presence of HNF1B-related extrarenal findings [Nakayama et al 2010, Sanna-Cherchi et al 2012, Madariaga et al 2013, Musetti et al 2014, Raaijmakers et al 2015, Westland et al 2015]. The individual studies reported rates of 0% to 6%.
  • 11% (42/377) in a study that included unrelated individuals with hyperechogenic kidneys with a size less than 3 SD above the mean, renal hypodysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with a UMOD pathogenic variant [Heidet et al 2010]
  • <1% in two cohorts not selected for severe renal disease, presence of HNF1B-related extrarenal phenotype, or family history:
    • 0.6% (1/178) in a consecutive series of all children with the full spectrum of severity of CAKUT who presented to tertiary referral centers [Caruana et al 2015]
    • 0.7% (3/419) in unselected children with mild to moderate chronic kidney disease (excluding ESRD, known cognitive deficits, structural heart disease, and clinically identifiable syndrome) [Verbitsky et al 2015]
• Müllerian aplasia: 6% (4/63) of women [Nik-Zainal et al 2011]. Among women with both uterine and renal anomalies, 18% had a HNF1B deletion or pathogenic sequence variant [Oram et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the 17q12 recurrent deletion syndrome, the following evaluations are recommended:

• Renal ultrasound examination; serum BUN, creatinine, electrolytes, calcium, magnesium, phosphorus, and uric acid; urine magnesium and creatinine; and consultation with a nephrologist
• Hemoglobin A1C and consultation with endocrinologist regarding possible evidence of maturity-onset diabetes of the young (MODY)
• Assessment of speech, cognitive development, motor development, and behavior
• Pelvic ultrasound examination and gynecologic examination in females to evaluate for possible müllerian abnormalities
• Liver function tests (AST, ALT, GGTP)
• Ophthalmologic examination
• Clinical assessment for congenital heart defects; consultation with a cardiologist and echocardiography if warranted
• Neurology consultation if seizure activity is suspected
• Audiologic screening
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is symptomatic and depends on an individual's specific needs.

Renal disease. Treatment should follow standard practice.

Established guidelines for the management of chronic kidney disease, including that related to CAKUT or ADTKD, are available for children and adults [KDIGO CKD Work Group 2013].

Some individuals have normal renal function, while others may progress to end-stage renal disease (ESRD) and require dialysis or kidney transplantation.

For those who have diabetes mellitus, simultaneous pancreas and kidney transplantation has been successful and should be considered [Faguer et al 2011, Halbritter et al 2011, Poitou et al 2012].

MODY5. Treatment should follow standard practice. The clinical course tends to be progressive in terms of hyperglycemia, requiring treatment with insulin [Fajans & Bell 2011].

Neurodevelopmental/neuropsychiatric disorders. Early identification and intervention for neurodevelopmental or neuropsychiatric disorders (e.g., global developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder) is important for optimal outcomes.

Specialized instruction and speech / occupational / physical / behavioral therapies should be provided if indicated.

Management of ASD should follow guidelines published by the American Academy of Pediatrics [Myers & Johnson 2007].

Psychiatric consultation and therapy is recommended for those with mental health concerns, such as mood disorders, anxiety, and/or psychosis.

Other. Cardiac, ophthalmologic, neurologic, gastrointestinal, and other conditions should be treated by the appropriate specialty according to standard guidelines.

Surveillance

Renal structure/function

• Renal ultrasound examination to monitor for kidney cysts 12 months after establishing the diagnosis, then every two to three years in childhood/adolescence and every three to five years in adulthood. If an abnormality is detected, more frequent ultrasound examinations may be warranted.
• Periodic monitoring of renal function; serum concentration of magnesium, potassium, uric acid; and possibly urine magnesium and creatinine, preferably under the guidance of a nephrologist. Annual or more frequent monitoring may be advised for patients who have laboratory findings suggesting renal impairment, are taking potentially nephrotoxic medications (e.g., nonsteroidal anti-inflammatory drugs), or have structural renal abnormalities [Verbitsky et al 2015]

MODY5

• HgbA1C annually
• Patients and families should be educated on how to monitor for the clinical signs and symptoms of diabetes mellitus (e.g., polyuria, polydipsia, weight loss [sometimes with polyphagia], fatigue, nausea, vomiting, and blurred vision) in order to promote early diagnosis and treatment.
  Note: Endocrinology consultations as indicated depending on an individual's clinical manifestations

Psychomotor development. Routine monitoring through early childhood. A full neuropsychological evaluation is indicated for children who experience difficulty with school.

Other. Audiologic and ophthalmological evaluations on a regular basis

Agents/Circumstances to Avoid

Individuals with HNF1B-associated renal disease, including the 17q12 recurrent deletion, who develop ESRD and require renal transplantation are at increased risk for developing new-onset diabetes after transplantation (NODAT); therefore, use of an immunosuppressive regimen that avoids tacrolimus and reduces corticosteroid exposure may be beneficial for those who do not have preexisting diabetes [Zuber et al 2009, Faguer et al 2011, Clissold et al 2015].

Evaluation of Relatives at Risk

If genomic testing detects the 17q12 recurrent deletion in one of the proband's parents, it is appropriate to clarify the genetic status of older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of renal structural or functional defects, maturity-onset diabetes of the young, and developmental delays/intellectual disability.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

The 17q12 recurrent deletion is inherited in an autosomal dominant manner, with approximately 70% of deletions occurring de novo and 30% inherited from a parent.

Risk to Family Members

Parents of a proband

• Evaluation of the parents by genomic testing to determine if they have the 17q12 recurrent deletion present in the proband is recommended. Because features range in severity, it is possible for parents who are mildly affected to be unaware of any clinical manifestations (diabetes and renal problems may not be evident until adulthood).
• Most studies examining the 17q12 recurrent deletion have not reported whether or not the parents were tested; therefore, inheritance status is often unknown or the data are limited. However, in 42 individuals with the deletion for whom this information is available, the deletion was de novo in 30 (71%) and inherited in 12 (29%).
• There is no evidence for parent-of-origin bias. The 17q12 recurrent deletion can be inherited from either parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.
• If the 17q12 recurrent deletion identified in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
• If one of the parents has the 17q12 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the full phenotypic expression in the individual.

Offspring of a proband. Offspring of an individual with the 17q12 recurrent deletion have a 50% chance of inheriting the deletion.

Other family members. The risk to other family members depends on the genetic status of the proband's parent: if a parent has the 17q12 recurrent deletion, his or her family members may also have the deletion (see Evaluation of Relatives at Risk).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 17q12 deletion syndrome.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Prenatal testing or preimplantation genetic diagnosis using genomic testing that will detect the 17q12 recurrent deletion may be an option to consider if:

• A parent has the 17q12 recurrent deletion.
• Neither parent has the 17q12 recurrent deletion but the couple is concerned about a recurrence in subsequent pregnancies after having had a child with the 17q12 recurrent deletion based on the theoretic possibility of parental germline mosaicism or other predisposing genetic mechanisms (presumed to be ~1%).

Pregnancies not known to be at increased risk for the 17q12 recurrent deletion. Prenatal CMA performed in follow up to indications other than a positive family history (e.g., fetal renal anomalies detected on ultrasound examination) may detect the 17q12 recurrent deletion [Hendrix et al 2012, Wapner et al 2012]. More recently, it has been suggested that testing for the 17q12 recurrent deletion should be offered when hyperechogenic kidneys of unknown cause are detected prenatally [Jones et al 2015].

Note: Regardless of whether the pregnancy is known or not known to be at increased risk for the 17q12 recurrent deletion syndrome, prenatal test results cannot reliably predict the phenotype.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Genetic Pathogenesis

The 17q12 deletion is recurrent, meaning that it involves the same unique genomic sequence. The 17q12 region is considered a hot spot for copy number variants, as it has specific molecular features (known as segmental duplications) that predispose to these events [Mefford et al 2007, Moreno-De-Luca et al 2010].

Deletion mechanism. The 17q12 genomic region involved in the recurrent 17q12 deletion is flanked on each side by segmental duplications which are highly repetitive segments of genomic material. Since these segmental duplications have a high degree of homology to one another, they can misalign during meiosis and give rise to deletions and duplications of the intervening genomic interval. This process, called non-allelic homologous recombination, accounts for the absence of the same unique genomic region in individuals with 17q12 recurrent deletion [Sharp et al 2006, Moreno-De-Luca et al 2010].

Genes of interest in this region. Genes within the 17q12 recurrent deletion region include: AATF, ACACA, C17orf78, DDX52, DHRS11, DUSP14, GGNBP2, HNF1B, LHX1, MRM1, MYO19, PIGW, SYNRG, TADA2A, and ZNHIT3.

Two genes are of particular interest with respect to phenotypes associated with the 17q12 recurrent deletion:

• HNF1B. HNF1B haploinsufficiency has been established as the cause of the renal, urogenital, and endocrine abnormalities that occur as part of the 17q12 recurrent deletion syndrome. Heterozygous pathogenic sequence variants in HNF1B cause renal cysts and diabetes (RCAD) syndrome, which is characterized by the combination of congenital anomalies of the kidney and urinary tract (CAKUT) and maturity onset diabetes of the young type 5 (MODY5) [Bingham et al 2001]. It has recently been established that haploinsufficiency does not appear to cause the cognitive and neuropsychiatric manifestations [Clissold et al 2016].
• LHX1. Heterozygous LHX1 likely pathogenic variants have been identified in females with müllerian aplasia/Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, though inheritance information was not available [Ledig et al 2011, Ledig et al 2012, Sandbacka et al 2013]. Because of its role in neural development, LHX1 also may contribute to the neurodevelopmental manifestations observed in the 17q12 recurrent deletion syndrome [Moreno-De-Luca et al 2010, Nagamani et al 2010].

Literature Cited

• Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LW, Long DA, Hennekam RC, Ledermann SE, Rees L, van't Hoff W, Marks SD, Trompeter RS, Tullus K, Winyard PJ, Cansick J, Mushtaq I, Dhillon HK, Bingham C, Edghill EL, Shroff R, Stanescu H, Ryffel GU, Ellard S, Bockenhauer D. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol. 2009;20:1123–31. [PMC free article: PMC2678044] [PubMed: 19389850]
• American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:S62–9. [PMC free article: PMC2797383] [PubMed: 20042775]
• Bellanné-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, Douillard C, Dubois-Laforgue D, Dusselier L, Gautier JF, Jadoul M, Laloi-Michelin M, Jacquesson L, Larger E, Louis J, Nicolino M, Subra JF, Wilhem JM, Young J, Velho G, Timsit J. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 2005;54:3126–32. [PubMed: 16249435]
• Bernardini L, Gimelli S, Gervasini C, Carella M, Baban A, Frontino G, Barbano G, Divizia MT, Fedele L, Novelli A, Béna F, Lalatta F, Miozzo M, Dallapiccola B. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports. Orphanet J Rare Dis. 2009;4:25. [PMC free article: PMC2777856] [PubMed: 19889212]
• Bingham C, Ellard S, Nicholls AJ, Pennock CA, Allen J, James AJ, Satchell SC, Salzmann MB, Hattersley AT. The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria. Diabetes. 2001;50:2047–52. [PubMed: 11522670]
• Bockenhauer D, Jaureguiberry G. HNF1B-associated clinical phenotypes: the kidney and beyond. Pediatr Nephrol. 2016;31:707–14. [PubMed: 26160100]
• Carroll RW, Murphy R. Monogenic diabetes: a diagnostic algorithm for clinicians. Genes (Basel). 2013;4:522–35. [PMC free article: PMC3927568] [PubMed: 24705260]
• Caruana G, Wong MN, Walker A, Heloury Y, Webb N, Johnstone L, James PA, Burgess T, Bertram JF. Copy-number variation associated with congenital anomalies of the kidney and urinary tract. Pediatr Nephrol. 2015;30:487–95. [PubMed: 25270717]
• Chen YZ, Gao Q, Zhao XZ, Chen YZ, Bennett CL, Xiong XS, Mei CL, Shi YQ, Chen XM. Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/maturity onset diabetes of the young type 5. Chin Med J (Engl). 2010;123:3326–33. [PubMed: 21163139]
• Cheroki C, Krepischi-Santos AC, Szuhai K, Brenner V, Kim CA, Otto PA, Rosenberg C. Genomic imbalances associated with mullerian aplasia. J Med Genet. 2008;45:228–32. [PubMed: 18039948]
• Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat Rev Nephrol. 2015;11:102–12. [PubMed: 25536396]
• Clissold RL, Shaw-Smith C, Turnpenny P, Bunce B, Bockenhauer D, Kerecuk L, Waller S, Bowman P, Ford T, Ellard S, Hattersley AT, Bingham C. Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder. Kidney Int. 2016;90:203–11. [PMC free article: PMC4915913] [PubMed: 27234567]
• Dixit A, Patel C, Harrison R, Jarvis J, Hulton S, Smith N, Yates K, Silcock L, McMullan DJ, Suri M. 17q12 microdeletion syndrome: three patients illustrating the phenotypic spectrum. Am J Med Genet A. 2012;158A:2317–21. [PubMed: 22887843]
• Eckardt KU, Alper SL, Antignac C, Bleyer AJ, Chauveau D, Dahan K, Deltas C, Hosking A, Kmoch S, Rampoldi L, Wiesener M, Wolf MT, Devuyst O. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report. Kidney Int. 2015;88:676–83. [PubMed: 25738250]
• Edghill EL, Oram RA, Owens M, Stals KL, Harries LW, Hattersley AT, Ellard S, Bingham C. Hepatocyte nuclear factor-1B- a common cause of renal disease. Nephrol Dial Transplant. 2008;23:627–35. [PubMed: 17971380]
• Faguer S, Bouissou F, Dumazer P, Guitard J, Bellane-Chentalot C, Chauveau D. Massively enlarged polycystic kidneys in monozygotic twins with TCF2/HNF-1B (hepatocyte nuclear factor-1B) heterozygous whole-gene deletion. Am J Kidney Dis. 2007;50:1023–7. [PubMed: 18037103]
• Faguer S, Decramer S, Chassaing N, Bellanne-Chantelot C, Calvas P, Beaufils S, Bessenay L, Lengele JP, Dahan K, Ronco P, Devuyst O, Chauveau D. Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood. Kidney Int. 2011;80:768–76. [PubMed: 21775974]
• Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care. 2011;34:1878–84. [PMC free article: PMC3142024] [PubMed: 21788644]
• George AM, Love DR, Hayes I, Tsang B. Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum. Mol Syndromol. 2012;2:72–5. [PMC free article: PMC3326281] [PubMed: 22511894]
• Goumy C, Laffargue F, Eymard-Pierre E, Kemeny S, Gaye-Bellile M, Gouas L, Gallot D, Francannet C, Tchirkov A, Pebrel-Richard C, Vago P. Congenital diaphragmatic hernia may be associated with 17q12 microdeletion syndrome. Am J Med Genet A. 2015;167A:250–3. [PubMed: 25425496]
• Grozeva D, Conrad DF, Barnes CP, Hurles M, Owen MJ, O'Donovan MC, Craddock N, Kirov G. Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia. Schizophr Res. Schizophr Res. 2012;135:1–7. [PMC free article: PMC3315675] [PubMed: 22130109]
• Haeri S, Devers PL, Kaiser-Rogers KA, Moylan VJ Jr, Torchia BS, Horton AL, Wolfe HM, Aylsworth AS. Deletion of hepatocyte nuclear factor-1-beta in an infant with prune belly syndrome. Am J Perinatol. 2010;27:559–63. [PubMed: 20175044]
• Halbritter J, Mayer C, Bachmann A, Rasche FM, Uhlmann D, Stumvoll M, Lindner TH. Successful simultaneous pancreas kidney transplantation in maturity-onset diabetes of the young type 5. Transplantation. 2011;92:e45–7. [PubMed: 21989275]
• Heidet L, Decramer S, Pawtowski A, Morinière V, Bandin F, Knebelmann B, Lebre AS, Faguer S, Guigonis V, Antignac C, Salomon R. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol. 2010;5:1079–90. [PMC free article: PMC2879303] [PubMed: 20378641]
• Hendrix NW, Clemens M, Canavan TP, Surti U, Rajkovic A. Prenatally diagnosed 17q12 microdeletion syndrome with a novel association with congenital diaphragmatic hernia. Fetal Diagn Ther. 2012;31:129–33. [PubMed: 22178801]
• Hinkes B, Hilgers KF, Bolz HJ, Goppelt-Struebe M, Amann K, Nagl S, Bergmann C, Rascher W, Eckardt K, Jacobi J. A complex microdeletion 17q12 phenotype in a patient with recurrent de novo membranous nephropathy. BMC Nephrol. 2012;13:27. [PMC free article: PMC3412739] [PubMed: 22583611]
• Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet. 1997;17:384–5. [PubMed: 9398836]
• Iwasaki N, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Yano N, Iwamoto Y. Liver and kidney function in Japanese patients with maturity-onset diabetes of the young. Diabetes Care. 1998;21:2144–8. [PubMed: 9839108]
• Jones GE, Mousa HA, Rowley H, Houtman P, Vasudevan PC. Should we offer prenatal testing for 17q12 microdeletion syndrome to all cases with prenatally diagnosed echogenic kidneys? Prenatal findings in two families with 17q12 microdeletion syndrome and review of the literature. Prenat Diagn. 2015;35:1336–41. [PubMed: 26429400]
• Kasperavičiūtė D, Catarino CB, Chinthapalli K, Clayton LMS, Thom M, Martinian L, Cohen H, Adalat S, Bockenhauer D, Pope SA, Lench N, Koltzenburg M, Duncan JS, Hammond P, Hennekam RCM, Land JM, Sisodiya SM. Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions. PLoS One. 2011;6:e23182. [PMC free article: PMC3157359] [PubMed: 21858020]
• KDIGO CKD Work Group. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Available online. 2013. Accessed 10-10-17.
• Laffargue F, Bourthoumieu S, Llanas B, Baudouin V, Lahoche A, Morin D, Bessenay L, De Parscau L, Cloarec S, Delrue M, Taupiac E, Dizier E, Laroche C, Bahans C, Yardin C, Lacombe D, Guigonis V. Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome. Arch Dis Child. 2015;100:259–64. [PubMed: 25324567]
• Ledig S, Schippert C, Strick R, Beckmann MW, Oppelt PG, Wieacker P. Recurrent abberations identifited by array-CGH in patients with Mayer-Rokitansky-Kuster-Hauser Syndrome. Fertil Steril. 2011;95:1589–94. [PubMed: 20797712]
• Ledig S, Brucker S, Barresi G, Schomburg J, Rall K, Wieacker P. Frame shift mutation of LHX1 is associated with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Hum Reprod. 2012;27:2872–5. [PubMed: 22740494]
• Loirat C, Bellane-Chantelot C, Husson I, Deschenes G, Guigonis V, Chabane N. Autism in three patients with cystic or hyperechogenic kidneys and chromosome 17q12 deletion. Nephrol Dial Transplant. 2010;25:3430–3. [PubMed: 20587423]
• Madariaga L, Morinière V, Jeanpierre C, Bouvier R, Loget P, Martinovic J, Dechelotte P, Leporrier N, Thauvin-Robinet C, Jensen UB, Gaillard D, Mathieu M, Turlin B, Attie-Bitach T, Salomon R, Gübler MC, Antignac C, Heidet L. Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin J Am Soc Nephrol. 2013;8:1179–87. [PMC free article: PMC3700697] [PubMed: 23539225]
• Mefford HC, Clauin S, Sharp AJ, Moller RS, Ullmann R, Kapur R, Pinkel D, Cooper GM, Ventura M, Ropers HH, Tommerup N, Eichler EE, Bellanne-Chantelot C. Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am J Hum Genet. 2007;81:1057–69. [PMC free article: PMC2265663] [PubMed: 17924346]
• Moreno-De-Luca D, Mulle JG, Kaminsky EB., SGENE Consortium. Simons Simplex Collection Genetics Consortium, Sanders SJ, GeneSTAR, Myers SM, Adam MP, Pakula AT, Eisenhauer NJ, Uhas K, Weik L, Guy L, Care ME, Morel CF, Boni C, Salbert BA, Chandrareddy A, Demmer LA, Chow EW, Surti U, Aradhya S, Pickering DL, Golden DM, Sanger WG, Aston E, Brothman AR, Gliem TJ, Thorland EC, Ackley T, Iyer R, Huang S, Barber JC, Crolla JA, Warren ST, Martin CL, Ledbetter DH. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet. 2010;87:618–30. [PMC free article: PMC2978962] [PubMed: 21055719]
• Musetti C, Quaglia M, Mellone S, Pagani A, Fusco I, Monzani A, Giordano M, Stratta P. Chronic renal failure of unknown origin is caused by HNF1B mutations in 9% of adult patients: a single centre cohort analysis. Nephrology. 2014;19:202–9. [PubMed: 24387224]
• Myers SM, Johnson CP. American Academy of Pediatrics Council on Children With Disabilities; Management of children with autism spectrum disorders. Pediatrics. 2007;120:1162–82. [PubMed: 17967921]
• Nagamani SCS, Erez A, Shen J, Li C, Roeder E, Cox S, Karaviti L, Pearson M, Kang SL, Sahoo T, Lalani SR, Stankiewicz P, Sutton VR, Cheung SW. Clinical spectrum associated with recurrent genomic rearrangements in chromosome 17q12. Eur J Hum Genet. 2010;18:278–84. [PMC free article: PMC2987224] [PubMed: 19844256]
• Nakayama M, Nozu K, Goto Y, Kamei K, Ito S, Sato H, Emi M, Nakanishi K, Tsuchiya S, Iijima K. HNF1B alterations associated with congenital anomalies of the kidney and urinary tract. Pediatr Nephrol. 2010;25:1073–9. [PubMed: 20155289]
• Nik-Zainal S, Strick R, Storer M, Huang N, Rad R, Willatt L, Fitzgerald T, Martin V, Sandford R, Carter NP, Janecke AR, Renner SP, Oppelt PG, Oppelt P, Schulze C, Brucker S, Hurles M, Beckmann MW, Strissel PL, Shaw-Smith C. High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia. J Med Genet. 2011;48:197–204. [PMC free article: PMC3322361] [PubMed: 21278390]
• Oram RA, Edghill EL, Blackman J, Taylor MJO, Kay T, Flanagan SE, Ismail-Pratt I, Creighton SM, Ellard S, Hattersley AT, Bingham C. Mutations in the hepatocyte nuclear factor-1B (HNF1B) gene are common with combined uterine and renal malformations but are not found with isolated uterine malformations. Am J Obstet Gynecol. 2010;203:364.e1–5. [PubMed: 20633866]
• Palumbo P, Antona V, Palumbo O, Piccione M, Nardello R, Fontana A, Carella M, Corsello G. Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case. Gene. 2014;538:373–8. [PubMed: 24487052]
• Poitou C, Francois H, Bellanne-Chantelot C, Noel C, Jacquet A, Clauin S, Beaudreuil S, Damieri H, Hebibi H, Hammoudi Y, Benoit G, Charpentier B, Durrbach A. Maturity onset diabetes of the young: clinical characteristics and outcome after kidney and pancreas transplantation in MODY3 and RCAD patients: a single center experience. Transpl Int. 2012;25:564–72. [PubMed: 22432796]
• Quintero-Rivera F, Woo JS, Bomberg EM, Wallace WD, Peredo J, Dipple KM. Duodenal atresia in 17q12 microdeletion including HNF1B: a new associated malformation in this syndrome. Am J Med Genet A. 2014;164A:3076–82. [PubMed: 25256560]
• Raaijmakers A, Corveleyn A, Devriendt K, van Tienoven TP, Allegaert K, Van Dyck M, van den Heuvel L, Kuypers D, Claes K, Mekahli D, Levtchenko E. Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract. Nephrol Dial Transplant. 2015;30:835–42. [PubMed: 25500806]
• Raile K, Klopocki E, Holder M, Wessel T, Galler A, Deiss D, Muller D, Riebel T, Horn D, Maringa M, Weber J, Ullmann R, Gruters A. Expanded clinical spectrum in hepatocyte nuclear factor 1B — maturity-onset diabetes of the young. J Clin Endocrinol Metab. 2009;94:2658–64. [PubMed: 19417042]
• Rasmussen M, Vestergaard EM, Graakjaer J, Petkov Y, Bache I, Fagerberg C, Kibaek M, Svaneby D, Petersen OB, Brasch-Andersen C, Sunde L. 17q12 deletion and duplication syndrome in Denmark- A clinical cohort of 38 patients and review of the literature. Am J Med Genet A. 2016;170:2934–42. [PubMed: 27409573]
• Roberts JL, Gandomi SK, Parra M, Lu I, Gau CL, Dasouki M, Butler MG. Clinical report of a 17q12 microdeletion with additionally unreported clinical features. Case Rep Genet. 2014;2014:264947. [PMC free article: PMC4060289] [PubMed: 24991439]
• Sandbacka M, Laivuori H, Freitas E, Halttunen M, Jokimaa V, Morin-Papunen L, Rosenberg C, Aittomaki K. TBX6, LHX1 and copy number variations in the complex genetics of Mullerian aplasia. Orphanet J Rare Dis. 2013;8:125. [PMC free article: PMC3847609] [PubMed: 23954021]
• Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, Nees SN, Verbitsky M, Perry BJ, Sterken R, Lozanovski VJ, Matema-Kiryluk A, Barlassina C, Kini A, Corbania V, Carrea A, Somenzi D, Murtas C, Ristoska-Bojkovska N, Izzi C, Bianco B, Zaniew M, Flogelova H, Weng PL, Kacak N, Giberti S, Gigante M, Arapovic A, Drnasin K, Caridi G, Curioni S, Allegri F, Ammenti A, Ferretti S, Goj V, Bernardo L, Jobanputra V, Chung WK, Lifton RP, Sanders S, State M, Clark LN, Saraga M, Padmanabhan S, Dominiczak AF, Foroud T, Gesualdo L, Gucev Z, Allegri L, Latos-Bielenska A, Cusi D, Scolari F, Tasic V, Hakonarson H, Ghiggeri GM, Gharavi AG. Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet. 2012;91:987–97. [PMC free article: PMC3516596] [PubMed: 23159250]
• Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, Price SM, Blair E, Hennekam RC, Fitzpatrick CA, Segraves R, Richmond TA, Guiver C, Albertson DG, Pinkel D, Eis PS, Schwartz S, Knight SJ, Eichler EE. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet. 2006;38:1038–42. [PubMed: 16906162]
• Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, Bjornsdottir G, Walters GB, Jonsdottir GA, Doyle OM, Tost H, Grimm O, Krisjansdottir S, Snorrason H, Davidsdottir SR, Gudmundsson LJ, Jonsson GF, Stefansdottir B, Helgadottir I, Haraldsson M, Jonsdottir B, Thygesen JH, Schwarz AJ, Didriksen M, Stensbol TB, Brammer M, Kapur S, Halldorsson JG, Hreidarsson S, Saemundsen E, Sigurdsson E, Stefansson K. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505:361–6. [PubMed: 24352232]
• van der Made CI, Hoorn EJ, de la Faille R, Karaaslan H, Knoers NV, Hoenderop JG, Vargas Poussou R, de Baaij JH. Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review. Am J Nephrol. 2015;42:85–90. [PubMed: 26340261]
• Verbitsky M, Sanna-Cherchi S, Fasel DA, Levy B, Kiryluk K, Wuttke M, Abraham AG, Kaskel F, Kottgen A, Warady BA, Furth SL, Wong CS, Gharavi AG. Genomic imbalances in pediatric patients with chronic kidney disease. J Clin Invest. 2015;125:2171–8. [PMC free article: PMC4463214] [PubMed: 25893603]
• Verhave JC, Bech AP, Wetzels JF, Nijenhuis T. Hepatocyte nuclear factor 1β-associated kidney disease: More than renal cysts and diabetes. J Am Soc Nephrol. 2016;27:345–53. [PMC free article: PMC4731131] [PubMed: 26319241]
• Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367:2175–84. [PMC free article: PMC3549418] [PubMed: 23215555]
• Westland R, Verbitsky M, Vukojevic K, Perry BJ, Fasel DA, Zwijnenburg PJ, Bökenkamp A, Gille JJ, Saraga-Babic M, Ghiggeri GM, D'Agati VD, Schreuder MF, Gharavi AG, van Wijk JA, Sanna-Cherchi S. Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney Int. 2015;88:1402–10. [PMC free article: PMC4834924] [PubMed: 26352300]
• Zuber J, Bellanne-Chantelot C, Carette C, Canaud G, Gobrecht S, Gaha K, Mallet V, Martinez F, Thervet E, Timsit J, Legendre C, Dubois-Laforgue D. HNF1B-related diabetes triggered by renal transplantation. Nat Rev Nephrol. 2009;5:480–4. [PubMed: 19639018]

Author Notes

Marissa Mitchel, MS, CCC-SLP

Scott Myers, MD, FAAP

Brenda Finucane, MS, LGC

David Ledbetter, PhD

Christa Lese Martin, PhD, FACMG

Geisinger Autism & Developmental Medicine Institute 17q12 Project
120 Hamm Drive, Suite 2
Lewisburg, PA 17837
Phone: 570-522-9430
Fax: 570-522-9431
www.geisingeradmi.org/17q12

Acknowledgments

This work was funded in part by the National Institute for Mental Health of the National Institutes of Health under awards RO1MH074090 (to DHL and CLM) and RO1MH107431 (to CLM) and grants from the Simons Foundation (SFARI# 215355 to CLM and SFARI# 240413 to DHL). The authors would also like to thank all of the individuals and families with 17q12 deletions for their participation in these research studies and Abby Hare-Harris, PhD, for assistance with the genotype/phenotype and penetrance sections.

Revision History

• 8 December 2016 (bp) Review posted live
• 10 August 2015 (mm) Original submission