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17q12 Recurrent Deletion Syndrome

, MS, CCC-SLP, , MD, MSc, , MD, , MS, LGC, , PhD, FACMG, and , PhD, FACMG.

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Summary

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.

Diagnosis

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

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.

Table 1.

Genomic Testing Used in the 17q12 Recurrent Deletion Syndrome

Deletion 1ClinGen ID 2Region Location 3, 4Test MethodTest Sensitivity
ProbandAt-risk family members
1.4-Mb heterozygous deletion at 17q12ISCA-37432GRCh37/hg19 chr17: 34815072-36192492CMA 5100%100%
Targeted deletion analysis 6Not applicable 7100% 8
1.

See Molecular Genetics for details of the deletion.

2.

Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays (ISCA) Consortium). The region is identified in dbVar (www​.ncbi.nlm.nih.gov/dbvar) as nsv491563.

3.

Genomic coordinates represent the minimum deletion size associated with the 17q12 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the recurrent 17q12 deletion (see Genetically Related Disorders).

4.

See Molecular Genetics for genes of interest included in this region.

5.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 17q12 region. Note: The 17q12 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.

6.

Targeted deletion analysis methods can include: FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.

7.

Targeted deletion analysis is not appropriate for an individual in whom the 17q12 recurrent deletion was not detected by CMA designed to target this region.

8.

Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 17q12 recurrent deletion.

Clinical Characteristics

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].

Table 2.

Clinical Features of the 17q12 Recurrent Deletion Syndrome

FrequencyFeatures
Most Common (>50%)Renal structural or functional defects
Neurodevelopmental / neuropsychiatric disorders
Mild dysmorphic features
Common (25%-50%)Maturity-onset diabetes of the young type 5 (MODY5)
Genital abnormalities
Liver abnormalities
Eye abnormalities
Nonspecific structural brain findings
Less Common (<25%)Other endocrine
Cardiac
Musculoskeletal
Gastrointestinal
Seizures
Macrocephaly
Congenital diaphragmatic hernia
Hypotonia
Sensorineural hearing loss
Hypoplastic, thick nails / onychodystrophy
Prenatal oligohydramnios

Most Common Features (>50%)

Renal disease. Structural kidney abnormalities and unspecified chronic kidney disease have been described in 125 individuals (Table 2). Cystic dysplastic kidneys and other structural renal anomalies are reported in 73/88 (83%) individuals who were not ascertained through cohorts with kidney disease, making this feature the most commonly reported manifestation of the 17q12 recurrent deletion syndrome.

Cystic renal dysplasia is the most common renal finding; other renal and urinary tract abnormalities include poor cortico-medullary differentiation, prenatal hyperechogenicity, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter, single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), duplex kidney, and horseshoe kidney.

Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine-concentrating ability, hyperuricemia, hypomagnesemia, hypokalemia, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, and slowly progressive renal disease; interstitial fibrosis and tubular atrophy are seen on biopsy (although biopsy is not routinely indicated) [Eckardt et al 2015, Verhave et al 2016]. Of note, autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by HNF1B haploinsufficiency (frequently due to 17q12 deletion) is designated ADTKD-HNF1B [Eckardt et al 2015].

Renal tubular wasting of magnesium resulting in hypomagnesemia is common and can be the initial and predominant manifestation of renal disease in individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Adalat et al 2009, Faguer et al 2011, Clissold et al 2015, Raaijmakers et al 2015, van der Made et al 2015].

The spectrum of severity and the age of detection of HNF1B-associated renal disease are broad, including prenatal severe renal failure, slow progression to end-stage renal disease (ESRD) in adulthood, and normal renal function never requiring renal replacement therapy [Edghill et al 2008, Haeri et al 2010, Heidet et al 2010, Faguer et al 2011, Madariaga et al 2013, Clissold et al 2015, Verhave et al 2016]. Available evidence suggests that the cause of HNF1B haploinsufficiency – 17q12 deletion, a HNF1B missense variant, or a HNF1B truncating variant (nonsense, frameshift, or splice site) – does not predict the type and severity of renal involvement [Heidet et al 2010, Faguer et al 2011, Raaijmakers et al 2015].

Progression to ESRD in childhood appears to be uncommon among individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Heidet et al 2010, Bockenhauer & Jaureguiberry 2016]. While small studies of selected cohorts of adults have suggested that 12%-15% of individuals may progress to ESRD, the true risk is largely unknown [Chen et al 2010, Faguer et al 2011].

Neurodevelopmental/neuropsychiatric disorders. Several studies have identified an increased risk for neurodevelopmental and neuropsychiatric disorders, such as developmental delay, intellectual disability (mild to severe), autism spectrum disorder (ASD), and schizophrenia [Loirat et al 2010, Moreno-De-Luca et al 2010, Nagamani et al 2010].

In a case-control study, Moreno-De-Luca et al [2010] identified the following number of individuals with the 17q12 recurrent deletion:

  • 18 of 15,749 individuals referred for developmental delay, intellectual disability, and/or ASD. Detailed phenotypic information for nine individuals revealed six with anxiety and/or phobias, one of whom was diagnosed with bipolar disorder. Because the 17q12 recurrent deletion was not detected in 4,519 controls, the authors concluded that the deletion confers a high risk for developmental brain disorders.
  • Four of 6,340 individuals from two large schizophrenia cohorts. Because the 17q12 recurrent deletion was not detected in 43,076 controls, the authors concluded that deletion also confers a high risk for schizophrenia.

Overall, 28/53 (53%) individuals with the 17q12 recurrent deletion are reported to have some degree of learning disability, although limited phenotypic information about cognitive skills was collected in most studies. Researchers report a diagnosis of intellectual disability in about 16% of individuals, while autistic features are described in 8% of individuals who were ascertained for other clinical findings.

Recent evidence suggests that genes other than HNF1B in the 17q12 region could be responsible for neurodevelopmental and neuropsychiatric features.

For instance, one study found that individuals with the recurrent 17q12 deletion, but not an HNF1B intragenic pathogenic variant, exhibited neurodevelopmental disorders, psychopathology, and autistic traits [Clissold et al 2016].The authors concluded that haploinsufficiency of HNF1B alone is not sufficient to result in the cognitive and behavioral features associated with the 17q12 recurrent deletion.

Dysmorphic features. Subtle, but highly variable, dysmorphic features are described for most individuals for whom this information is available. The most commonly described features include high forehead, frontal bossing, depressed nasal bridge, deep-set eyes, full cheeks, downslanting palpebral fissures, and high-arched eyebrows [Moreno-De-Luca et al 2010, Dixit et al 2012, Quintero-Rivera et al 2014, Goumy et al 2015, Laffargue et al 2015, Rasmussen et al 2016].

Hypoplastic nails, 2-3 finger/toe syndactyly, and clinodactyly of the 5th finger are also frequently reported [Moreno-De-Luca et al 2010, Kasperavičiūtė et al 2011, Palumbo et al 2014].

Common Features (25%-50%)

Maturity-onset diabetes of the young type 5 (MODY5) is most often diagnosed before age 25 years (range: 10-50 years) [Bellanné-Chantelot et al 2005].

Overt diabetes mellitus and abnormal blood glucose levels and/or insulin response are reported in 28/70 (40%) individuals with the 17q12 recurrent deletion not ascertained from cohorts with diabetes mellitus; however, this is almost certainly an underestimate of the lifetime prevalence, since many individuals described in the literature are children and young adults who may not yet have developed manifestations of diabetes. When cohorts with diabetes mellitus are considered, prevalence of MODY5 among individuals with the 17q12 recurrent deletion is well over 50%.

Genital abnormalities. About one third of females and 25% of males have genital abnormalities.

In females, the most commonly reported finding is partial or complete absence of the upper part of the vagina, cervix, and uterus, often referred to as müllerian aplasia or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [Bernardini et al 2009]. Other reported uterine abnormalities include bicornuate uterus, uterus didelphys, and hypoplastic uterus [Oram et al 2010].

In males, genital abnormalities include cryptorchidism [Mefford et al 2007, Raile et al 2009, Haeri et al 2010], shawl scrotum [Nagamani et al 2010], phimosis [Edghill et al 2008], urethral stenosis [Moreno-De-Luca et al 2010], and coronal hypospadias [Dixit et al 2012].

Liver. Elevated liver enzymes were reported in 29/73 (40%) individuals in cohorts ascertained for renal involvement, diabetes mellitus, and uterine malformations [Bellanné-Chantelot et al 2005, Mefford et al 2007, Edghill et al 2008, Oram et al 2010, Quintero-Rivera et al 2014, Rasmussen et al 2016]. Additional reported liver abnormalities included cysts, hepatomegaly, cholestasis, and steatohepatitis [Raile et al 2009, Rasmussen et al 2016].

Eye abnormalities. Twelve of 33 (36%) reported individuals had eye findings that included strabismus [Rasmussen et al 2016], horizontal nystagmus [Cheroki et al 2008], posterior embryotoxon [Dixit et al 2012], hypermetropia [Moreno-De-Luca et al 2010], cataracts [Nagamani et al 2010], and coloboma [Raile et al 2009].

Nonspecific structural brain findings. Structural brain anomalies were reported in seven of 28 (25%) individuals. These abnormalities, which appeared to be nonspecific and to vary widely, included the following:

Less Common Features (<25%)

Other endocrine. Pancreatic abnormalities (most often atrophy or small size) were reported in 10/50 (20%) individuals [Mefford et al 2007, Edghill et al 2008].

In one study three infants had neonatal hypercalcemia [Dixit et al 2012]. In another study two of 17 individuals had hypothyroidism [Edghill et al 2008].

Cardiac. Congenital heart defects, reported in seven of 31 individuals, ranged from mild (soft systolic murmur [Dixit et al 2012]) to more severe (right heart failure with tricuspid valve insufficiency [Hinkes et al 2012]). Other reported cardiac anomalies included increased aortic root size, transposition of the great arteries, pulmonary valve defect, and patent ductus arteriosus.

Musculoskeletal. Seven of 25 (28%) individuals were reported to have short stature. Other musculoskeletal differences include joint laxity (4 persons), long/slender hands and feet (4), pectus deformity (3), long fingers (2), and hip dysplasia (1).

Gastrointestinal. Gastroesophageal reflux disease (GERD) was reported in three individuals [Moreno-De-Luca et al 2010, Goumy et al 2015, Rasmussen et al 2016]. One individual had duodenal atresia [Quintero-Rivera et al 2014] and two had esophageal abnormalities, including hiatus hernia caused by a short esophagus and dysphagia [Rasmussen et al 2016].

Other reported physical findings include hypotonia (6 persons), seizures (4), prenatal oligohydramnios (4), macrocephaly (4), sensorineural hearing loss (3), and congenital diaphragmatic hernia (2).

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].

Differential Diagnosis

Renal anomalies. The differential diagnosis of renal cysts is age dependent. For prenatally diagnosed bilateral enlarged, hyperechogenic kidneys, the most common disorders in the differential are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD).

In children, the differential diagnosis of renal cysts includes early-onset ADPKD, ARPKD, idiopathic cystic dysplasia, nephronophthisis, obstructive dysplasia, and tuberous sclerosis complex [Clissold et al 2015]. In adults, renal cysts may be acquired (related to chronic renal impairment and/or dialysis), simple cortical cysts, or cysts associated with ADPKD, ARPKD, or von Hippel-Lindau syndrome [Clissold et al 2015].

The differential diagnosis of autosomal dominant tubulointerstitial kidney disease (ADTKD) includes the following genetic disorders [Eckardt et al 2015]:

  • ADTKD-MUC1 (previously known as mucin-1 kidney disease [MKD] or medullary cystic kidney disease type 1 [MCKD1])
  • ADTKD-UMOD (previously known as UMOD-associated kidney disease [UAKD], familial juvenile hyperuricemic nephropathy type 1 [FJHN1], medullary cystic kidney disease type 2 [MCKD2], or uromodulin kidney disease [UKD])
  • ADTKD-REN (previously known as familial juvenile hyperuricemic nephropathy type 2)

Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders of pancreatic β-cell function characterized by impaired glucose-stimulated insulin secretion which occurs in individuals younger than age 25 years (Table 3). All are inherited in an autosomal dominant manner.

The clinical findings are either:

  • An atypical type-2 diabetes-like condition that occurs in the absence of the usual predisposing factors (obesity, hypertension, dyslipidemia, and acanthosis nigricans); OR
  • An atypical type 1 diabetes-like condition that occurs in the absence of the usual clinical and laboratory manifestations (islet cell autoantibodies, persistence of measurable C-peptide levels, and diabetic ketoacidosis) [American Diabetes Association 2010, Fajans & Bell 2011, Carroll & Murphy 2013].

Table 3.

Maturity-Onset Diabetes of the Young (MODY) Subtypes

Subtype (OMIM)Gene (Alias)
MODY1 (125850)HNF4A
MODY2 (125851)GCK
MODY3 (600496)HNF1A
MODY4 (606392)PDX1
MODY5 1 (137920)HNF1B
MODY6 (606394)NEUROD1 (BETA2)
MODY7 (610508)KLF11
MODY8 (609812)CEL
MODY9 (612225)PAX4
MODY10 (613370)INS
MODY11 (613375)BLK
MODY13 (616329)KCNJ11
MODY14 (616511)APPL1
1.

Also referred to as renal cysts and diabetes (RCAD) syndrome

Other genetic causes of müllerian aplasia. Six percent of women in a large cohort with müllerian aplasia had the 17q12 recurrent deletion; an additional 8% had other recurrent copy number variants, including the 16p11.2 recurrent deletion and the distal 22q11.2 recurrent deletion [Nik-Zainal et al 2011].

Other genetic causes of neurodevelopmental or neuropsychiatric disorders. The differential diagnosis for developmental delay, intellectual disability, and autism spectrum disorder includes hundreds of known copy number and single-nucleotide variants and is too broad for discussion here.

Macrocephaly. Although macrocephaly is a less common feature of the 17q12 recurrent deletion, the co-occurrence of autism spectrum disorder and macrocephaly should raise suspicion for the 17q12 recurrent deletion as well as other pathogenic variants or CNVs associated with this combination, such as mutation of NSD1 (Sotos syndrome), PTEN tumor hamartoma syndrome, and the 16p11.2 recurrent deletion.

Management

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Chromosome Disorder Outreach (CDO)
    PO Box 724
    Boca Raton FL 33429-0724
    Phone: 561-395-4252 (Family Helpline)
    Email: info@chromodisorder.org
  • Unique: The Rare Chromosome Disorder Support Group
    G1 The Stables
    Station Road West
    Oxted Surrey RH8 9EE
    United Kingdom
    Phone: +44 (0) 1883 723356
    Email: info@rarechromo.org; rarechromo@aol.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

17q12 Recurrent Deletion Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
HNF1B17q12Hepatocyte nuclear factor 1-betaHNF1B databaseHNF1BHNF1B

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for 17q12 Recurrent Deletion Syndrome (View All in OMIM)

137920RENAL CYSTS AND DIABETES SYNDROME; RCAD
189907HNF1 HOMEOBOX B; HNF1B
614527CHROMOSOME 17q12 DELETION SYNDROME

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].

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Chapter Notes

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
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