17q12 Recurrent Deletion Syndrome

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2021-01-18
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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., 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 and functional kidney anomalies occur in 85% to 90% 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: age 10-50 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 kidney anomalies, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, eye abnormalities, congenital heart defects, seizures and sensorineural hearing loss should follow standard practice.

Surveillance: Kidneys and urinary tract: In the absence of known structural abnormalities, kidney and bladder 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 kidney function in individuals with abnormalities detected on kidney ultrasound examination; more frequent monitoring may be advised in those taking potentially nephrotoxic medications and/or known to have impaired kidney function. Routine monitoring of neurodevelopment through early childhood; full neuropsychological evaluation for children who experience difficulty with school. HbA1C annually to monitor for MODY5; self-monitoring by individuals and their families for clinical signs and symptoms of diabetes mellitus, such as polydipsia and polyuria. Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea. Consider annual hepatic function panel (or comprehensive metabolic panel), GGT, and lipid panel. Annual ophthalmologic evaluation during early childhood. Monitor those with seizures as clinically indicated. Hearing screening throughout childhood.

Agents/circumstances to avoid: Because kidney transplantation increases the risk for post-transplant diabetes mellitus, an immunosuppressive regimen that avoids tacrolimus and mammalian target of rapamycin (mTOR) inhibitors and reduces corticosteroid exposure may benefit those without preexisting diabetes mellitus. Nephrotoxic and hepatotoxic drugs should be avoided by individuals with kidney or liver abnormalities. For individuals with mental health conditions such as autism, schizophrenia, or bipolar disorder, careful consideration of antipsychotic agents that may lead to weight gain is recommended, as this potential increase has been associated with metabolic syndrome and the later development of diabetes mellitus, for which people with 17q12 deletions are at baseline increased risk. Likewise, the use of mood stabilizers that affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional abnormalities in people with 17q12 deletions.

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 genitourinary 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 75% of deletions occurring de novo and approximately 25% 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 testing 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 clinical and laboratory findings.

Clinical findings

  • Kidney abnormalities
    • Congenital abnormalities of the kidney and urinary tract (CAKUT), including the following:
      • Abnormalities on prenatal imaging including hyperechogenicity or poor corticomedullary differentiation
      • Abnormalities of kidney parenchyma including hypoplasia, dysplasia, multicystic dysplastic kidney (MCDK), or agenesis
      • Fusion anomalies (e.g., horseshoe kidney)
      • Collecting system abnormalities, including duplicated collecting systems, ureteropelvic junction obstruction, isolated hydronephrosis, or hydroureter
    • Tubulointerstitial disease, characterized by reduced urine concentrating ability with bland urinary sediment, absent-to-minimal albuminuria/proteinuria, hyperuricemia, hypomagnesemia, hypokalemia, and tubulointerstitial fibrosis on kidney histology. In some cases, hypomagnesemia is the initial and predominant symptom of kidney 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., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder)
  • Müllerian aplasia / Mayer-Rokitansky-Küster-Hauser syndrome in females

Note: The combination of kidney or urogenital anomalies with MODY has been referred to as renal cysts and diabetes (RCAD) syndrome.

Laboratory findings. The 17q12 recurrent deletion syndrome should be suspected in individuals with a 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 (see Table 1 and Molecular Genetics).

For this GeneReview, the 17q12 recurrent deletion is defined as the presence of a recurrent 1.4-Mb deletion at the approximate position of 36,458,167-37,854,616 in the reference genome (NCBI Build GRCh38/hg38).

ISCN nomenclature for this deletion is: seq[GRCh37] del(17)(q12) chr17:g. 36,458,16737,854,616del. 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 in the 17q12 region see Molecular Genetics.

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA), exome sequencing with CNV calling, genome sequencing, or targeted deletion analysis. Note: The 17q12 recurrent deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

CMA using oligonucleotide or SNP arrays can detect the recurrent deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 17q12 region.

Note: (1) Most individuals with the 17q12 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2007, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.

Exome and genome sequencing analyses are next-generation sequencing technologies that generate DNA sequence either for all coding regions (exome) or the entire genome. Copy number variant-calling algorithms need to be utilized to detect the 17q12 recurrent deletion.

Targeted deletion analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband who is known to have the 17q12 recurrent deletion. Virtually all whole-gene deletions of HNF1B identified by gene-targeted deletion/duplication analysis have been shown to include the entire 17q12 recurrent deletion region [Laffargue et al 2015], which can be confirmed using CMA.

Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 17q12 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.

Table 1.

Genomic Testing Used in 17q12 Recurrent Deletion Syndrome

Deletion 1MethodSensitivity
ProbandAt-risk family
members
1.4-Mb heterozygous deletion at 17q12
ISCN: seq[GRCh38] del(17)(q12)
chr17:g. 36,458,167-37,854,616del 2
ClinGen ID: ISCA-37432		CMA 3100%100%
Exome & genome
sequencing 4		100%100%
Targeted deletion
analysis 5		NA 6100% 7
1.

See Molecular Genetics for details of the deletion and genes of interest included in the region.

2.

Standardized ISCN 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. 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).

3.

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.

4.

Copy number variant-calling algorithms need to be utilized to detect the 17q12 recurrent deletion.

5.

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

6.

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.

7.

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

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 17q12 recurrent deletion in at-risk relatives of the proband. Testing of parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Characteristics

Clinical Description

The 17q12 recurrent deletion syndrome is characterized by variable combinations of the following three most common findings: kidney 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., 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 282 individuals on whom sufficiently detailed phenotypic information was reported in 42 studies (Table 2) using the following criteria:

  • To minimize ascertainment bias, studies involving disease-specific cohorts were not included in the prevalence calculations of that particular phenotypic manifestation (e.g., kidney anomalies).
  • 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.

17q12 Recurrent Deletion Syndrome: Frequency of Select Features

FrequencyFeatures
Most common (>50%)
  • Kidney structural or functional defects
  • Neurodevelopmental/neuropsychiatric disorders
  • Mild dysmorphic features
  • Hyperparathyroidism
Common (25%-50%)
  • Maturity-onset diabetes of the young type 5
  • Female & male genital abnormalities
  • Structural & functional liver abnormalities
  • Eye abnormalities
  • Structural &exocrine abnormalities of the pancreas
  • Nonspecific structural brain findings
  • Prematurity
Less common (<25%)
  • Congenital cardiac anomalies
  • Musculoskeletal features
  • Other gastrointestinal features
  • Seizures

Clinical data summarized from 42 studies, including 282 individuals in whom the 17q12 recurrent deletion was identified [Bellanné-Chantelot et al 2005, Faguer et al 2007, Mefford et al 2007, Cheroki et al 2008, Edghill et al 2008, Bernardini et al 2009, Raile et al 2009, Loirat et al 2010, Moreno-De-Luca et al 2010, Nagamani et al 2010, Oram et al 2010, Kasperavičiūtė et al 2011, Nik-Zainal et al 2011, Dixit et al 2012, George et al 2012, Grozeva et al 2012, Hendrix et al 2012, Hinkes et al 2012, Sanna-Cherchi et al 2012, Ferrè et al 2013, Palumbo et al 2014, Quintero-Rivera et al 2014, Roberts et al 2014, Stefansson et al 2014, Goumy et al 2015, Laffargue et al 2015, Verbitsky et al 2015, Rasmussen et al 2016, Dubois-Laforgue et al 2017a, Madariaga et al 2018, Roehlen et al 2018, Stiles et al 2018, Dotto et al 2019, Li et al 2019, Okorn et al 2019, Vasileiou et al 2019, Berberich et al 2020, Bustamante et al 2020, Du et al 2020, Kołbuc et al 2020, Lim et al 2020, Sztromwasser et al 2020]

Most Common Features (>50%)

Kidney disease. Structural kidney abnormalities and unspecified chronic kidney disease have been described in 257 individuals (Table 2). Cystic dysplastic kidneys and other structural kidney anomalies are reported in 130/148 (88%) 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 dysplasia is the most common kidney finding; other kidney and urinary tract abnormalities include poor cortico-medullary differentiation, collecting system abnormalities (duplicated collecting system, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter), single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), and horseshoe kidney.

Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine concentrating ability, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, hyperuricemia, hypomagnesemia, hypokalemia, and slowly progressive kidney 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].

Tubular wasting of magnesium resulting in hypomagnesemia is common and can be the initial and predominant manifestation of kidney disease in individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Clissold et al 2015, Raaijmakers et al 2015, van der Made et al 2015]. Hypomagnesemia is reported in 36/81 (44%) individuals with 17q12 recurrent deletion and can be severe [Ferrè et al 2013, Madariaga et al 2018, Dotto et al 2019, Li et al 2019, Okorn et al 2019, Berberich et al 2020]. Some studies suggest that hypomagnesemia may be underdiagnosed among children with HNF1B-related disorders, including 17q12 recurrent deletion [Kołbuc et al 2020]. Tubular magnesium wasting can be diagnosed through an elevated fractional excretion of magnesium (FEMg >2%) in individuals with normal kidney function.

The spectrum of severity and range in age of detection of HNF1B-associated kidney disease are broad, including prenatal severe kidney failure, slow progression to end-stage renal disease (ESRD) in adulthood, and normal kidney function never requiring kidney replacement therapy [Madariaga et al 2013, Clissold et al 2015, Verhave et al 2016]. While initial evidence suggested that the cause of HNF1B haploinsufficiency – 17q12 deletion, a HNF1B missense variant, or a HNF1B truncating variant (nonsense, frameshift, or splice site) – did not predict the type and severity of kidney involvement [Raaijmakers et al 2015], more recent evidence indicates that intragenic HNF1B pathogenic variants may be associated with worse kidney function and higher risk of progression to ESRD compared to 17q12 deletions [Dubois-Laforgue et al 2017b, Clissold et al 2018]. The reason for this finding is unknown, but the authors speculate a possible dominant-negative effect of certain HNF1B variants resulting in a more severe phenotype, or a protective effect conferred by the loss of one or more genes in the 17q12 recurrent deletion region.

Progression to ESRD in childhood appears to be uncommon among individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Bockenhauer & Jaureguiberry 2016]. In a large retrospective cohort study, progression to ESRD was less common among adults with 17q12 deletion at follow-up (51%) compared with those with HNF1B intragenic mutations (78%) [Dubois-Laforgue et al 2017b].

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 [Moreno-De-Luca et al 2010, Laliève et al 2020].

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

  • Eighteen 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, about half (37/79) of individuals with the 17q12 recurrent deletion are reported to have some degree of learning disability, although phenotypic information about cognitive skills was limited in most studies. Speech and motor delay are common findings, reported in 78% and 68% of individuals, respectively. While not routinely assessed, autism or autistic features are described in 9% of individuals ascertained for other clinical findings [Raile et al 2009, Loirat et al 2010, Dixit et al 2012, Palumbo et al 2014, Roberts et al 2014, Goumy et al 2015, Laffargue et al 2015, Rasmussen et al 2016, Li et al 2019, Vasileiou et al 2019, Lim et al 2020]. Learning difficulties, when noted, are most often described as mild. One study found that only 14/110 (12.7%) children with the 17q12 recurrent deletion required special school placement, which the researchers used as a proxy for severe neuropsychiatric disorder [Laliève et al 2020].

Some studies suggest that genes other than HNF1B in the 17q12 region could be responsible for neurodevelopmental and neuropsychiatric features, although evidence is mixed. 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]; however, other studies have found that both groups of HNF1B-related disorders are associated with an increased risk of intellectual disability [Dubois-Laforgue et al 2017a, Laliève et al 2020]. While haploinsufficiency of HNF1B alone may not be sufficient to result in the cognitive and behavioral features associated with the 17q12 recurrent deletion, the role of HNF1B in neurologic impairment cannot be ruled out.

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, high palate, and high-arched eyebrows [Moreno-De-Luca et al 2010, Laffargue et al 2015, Rasmussen et al 2016, Roehlen et al 2018, Vasileiou et al 2019].

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

Hyperparathyroidism. Nineteen of 36 (53%) individuals who had parathyroid hormone plasma levels tested were found to have hyperparathyroidism [Ferrè et al 2013, Li et al 2019, Berberich et al 2020, Kołbuc et al 2020, Lim et al 2020]. Furthermore, one study reported transient neonatal hypercalcemia and hypophosphatemia, the combination of which is suggestive of hyperparathyroidism, although PTH levels were not specifically measured to confirm [Dixit et al 2012]. Another study demonstrated that HNF1B is expressed in the parathyroid gland and acts as a transcriptional repressor of PTH [Ferrè et al 2013]. Additionally, this study found that PTH levels remained increased even after kidney transplantation and normalized magnesium levels in some patients. Although hyperparathyroidism is persistent in 20%-50% of individuals who are post-transplant independent of genetics, the authors concluded that the weight of the evidence suggests that HNF1B haploinsufficiency causes hyperparathyroidism independent of associated kidney failure.

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 49/125 (39%) 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 50%.

While many individuals with 17q12 deletion with MODY5 have some residual insulin secretion at the time of diagnosis, one study found that 79% required insulin therapy by ten-year follow up [Dubois-Laforgue et al 2017b].

Genital abnormalities. About one third of females and one quarter 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 syndrome [Bernardini et al 2009]. Other reported uterine abnormalities include bicornuate uterus, uterus didelphys, hypoplastic uterus, and ovarian cysts [Oram et al 2010, Stiles et al 2018, Vasileiou et al 2019].

In males, genital abnormalities include cryptorchidism, shawl scrotum, phimosis, urethral stenosis or obstruction, hypospadias, and epydidimary cysts [Nagamani et al 2010, Madariaga et al 2018, Lim et al 2020].

Structural and functional abnormalities of the liver. Elevated liver enzymes were reported in 64/133 (48%) individuals in cohorts ascertained for kidney involvement, diabetes mellitus, and uterine malformations [Rasmussen et al 2016, Dubois-Laforgue et al 2017a, Okorn et al 2019]. Liver involvement ranges from asymptomatic elevation of hepatic transaminase enzyme levels to neonatal and adult-onset cholestasis [Kotalova et al 2015, Pinon et al 2019]. Neonatal cholestasis with paucity of interlobular bile ducts and variable periportal fibrosis has also been reported in several infants with 17q12 recurrent deletion, including one who required portoenterostomy and one who developed hepatocellular carcinoma requiring liver transplantation [Pinon et al 2019]. Additional reported liver abnormalities include choledochal and common bile duct cysts, hepatomegaly, and steatohepatitis [Roehlen et al 2018, Lim et al 2020]. One study reported an even higher frequency of abnormal liver function tests (71%) in a large cohort that included both intragenic HNF1B variants and 17q12 deletions [Dubois-Laforgue et al 2017b]. While the study’s authors did not differentiate between genotypes, no statistically significant genotype/phenotype correlations were reported, suggesting that elevated LFTs may be even more common (>50%).

Eye abnormalities. Fifteen of 37 (41%) reported individuals had eye findings that included strabismus [Vasileiou et al 2019], 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].

Structural and exocrine abnormalities of the pancreas. About one third (32/105) of individuals with imaging results were found to have some morphologic abnormality of the pancreas, most often hypoplasia, atrophy, and/or agenesis of the body and tail [Madariaga et al 2018, Roehlen et al 2018, Dotto et al 2019, Kołbuc et al 2020].

One retrospective cohort study involving both 17q12 deletions and HNF1B sequence variants found pancreatic exocrine insufficiency in 29/38 cases (76%) and structural pancreatic abnormalities in 62% of 95 patients who had imaging [Dubois-Laforgue et al 2017b]. The study’s authors did not differentiate between the groups of patients, but reported no significant genotype/phenotype differences for this feature. Most other studies did not measure fecal elastase, but those that did reported a lower frequency of pancreatic exocrine insufficiency (2 of 8 cases) [Raile et al 2009, Quintero-Rivera et al 2014, Roehlen et al 2018].

Prematurity. Among 16 studies that reported premature birth (gestational age <37 weeks), 13 of 47 individuals (28%) were affected.

Nonspecific structural brain findings. No systematic neuroimaging studies of cohorts with 17q12 recurrent deletion syndrome have been published. Among publications describing neuroimaging findings, structural brain anomalies were reported in eight of 31 (26%) individuals. These abnormalities, which appeared to be nonspecific and to vary widely, included the following:

  • Ventricular dilatation [Vasileiou et al 2019]
  • Mild cerebellar atrophy [Kasperavičiūtė et al 2011]
  • Abnormal signal intensity of subcortical white matter [Moreno-De-Luca et al 2010]
  • Atrophy of the hippocampus [Nagamani et al 2010]

Less Common Features (<25%)

Congenital cardiac anomalies. Congenital heart defects are reported in nine of 45 (20%) individuals, ranging from mild to severe. Cardiac anomalies include right heart failure with tricuspid valve insufficiency, increased aortic root size, aortic insufficiency, coarctation of the aorta, ventricular septal defect, transposition of the great arteries, pulmonary valve defect, tricuspid regurgitation, and patent ductus arteriosus [Hinkes et al 2012, Palumbo et al 2014, Roberts et al 2014, Vasileiou et al 2019, Du et al 2020].

Musculoskeletal. Nine of 39 (23%) individuals were reported to have short stature. Other musculoskeletal differences include joint laxity (5 persons), long/slender hands and feet (4), pectus deformity (3), fifth finger clinodactyly (3), single transverse palmar crease (1), and hip dysplasia (1).

Other gastrointestinal features. Gastroesophageal reflux disease 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].

Seizures. Seven out of 50 cases (14%) reported seizure activity, including febrile seizures [Moreno-De-Luca et al 2010], partial complex seizures [Nagamani et al 2010], and mesial temporal lobe epilepsy requiring lobectomy [Kasperavičiūtė et al 2011].

Case Reports

Other reported physical findings include hypotonia (6 persons), prenatal oligohydramnios (4), macrocephaly (4), sensorineural hearing loss (3), deep vein thrombosis/vascular calcifications (2) 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 [Moreno-De-Luca et al 2010, George et al 2012, Quintero-Rivera et al 2014, Dotto et al 2019, Okorn et al 2019, Kołbuc et al 2020]. Although the size of the deletion did not differ between parents and children in these reports, significant variability in clinical presentation has been reported both between and within phenotype categories.

Penetrance

The 17q12 recurrent deletion is highly pathogenic and penetrant, but expressivity is variable.

Because population-based studies with evaluation of all individuals with a 17q12 recurrent deletion are lacking, the exact penetrance is unknown both for individual phenotypic categories (e.g., kidney anomalies, neurodevelopmental disorders, diabetes) and for the presence of any associated pathologic phenotype (e.g., kidney anomaly OR neurodevelopmental disorder OR diabetes).

However, high pathogenicity and penetrance is supported by several lines of evidence:

  • High rate of structural kidney anomalies among individuals who were not ascertained as part of kidney disease cohorts (130/148; 88%) (Table 2)
  • Preliminary evidence suggesting a high rate of neurodevelopmental and neuropsychiatric disorders among individuals who were not ascertained as part of NDD/NPD cohorts (3/4; 75%) [Martin et al 2020]
  • Very low frequency of the deletion in control populations (e.g., none in ~48,000 controls in one study [Moreno-De-Luca et al 2010])
  • High de novo ratio (percentage of cases that are de novo) [Kirov et al 2014]

These studies suggest that penetrance is virtually 100%, with missing data and variable expressivity accounting for the very rare presence of the 17q12 deletion in control populations.

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

The reported prevalence of the 17q12 recurrent deletion in large populations not selected on the basis of disease ranges from 0.002% (1:50,000) to 0.007% (1:14,000) – 0.002% in healthy European volunteers (UK Biobank; n = ~421K), 0.004% in a US health care system-based population (DiscovEHR; n = ~90K), and 0.007% in a large Icelandic control sample (deCODE; n = ~101K) [Martin et al 2020]. A higher prevalence estimate of 0.025% (1:4,000) was described in a population-based pregnancy cohort study of 12,252 mother-father-newborn trios [Smajlagić et al 2020].

Among individuals undergoing clinical postnatal chromosomal microarray analysis, the prevalence of the 17q12 recurrent deletion is much higher: approximately 0.1% (1:1000) [Moreno-De-Luca et al 2010, Rosenfeld et al 2013, Kirov et al 2014, Rasmussen et al 2016]. The main indications for clinical CMA in these studies were neurodevelopmental disorders (global developmental delay, intellectual disability, ASD) and congenital malformations.

It may be useful to consider the estimated prevalence of the 17q12 recurrent deletion in certain clinical populations:

  • Congenital anomalies of the kidney. 1.9% (~1:53); when considering CAKUT more broadly, 0.8% (~1:123) have 17q12 deletion [Verbitsky et al 2019].
  • Chronic kidney disease. 0.03%-2.2% (~1:3000 - 1:46) [Lata et al 2018, Connaughton et al 2019, Groopman et al 2019]
  • Neurodevelopmental disorders. 0.09% (~1:1,150) [Kirov et al 2014]
  • Schizophrenia. 0.036% (~1:2,800) [Kirov et al 2014]
  • Müllerian aplasia. 3%-6% (~1:33 - 1:17) [Nik-Zainal et al 2011, Williams et al 2017]. Among women with both uterine and kidney anomalies, 18% (~1:6) had a 17q12 deletion or pathogenic HNF1B sequence variant [Oram et al 2010].

Differential Diagnosis

Kidney anomalies. The differential diagnosis of kidneys cysts is age dependent (see Table 3).

Table 3.

Genetic Disorders with Kidney Cysts in the Differential Diagnosis of 17q12 Recurrent Deletion Syndrome

Gene(s)DisorderMOIKidney PhenotypeExtrarenal Phenotype
DNAJB11
GANAB
PKD1
PKD2		ADPKDADNumerous bilateral cysts; kidney enlargement; hypertension; nephrolithiasis; progressive CKD, w/ESRD in mid- to late-adulthood. DNAJB11- & GANAB-assoc disease have milder phenotypes w/normal-sized kidneys, smaller cysts, & less progression to ESRD.Liver cysts; intracranial aneurysms; cardiac valve abnormalities; diverticular disease; hernias
ALG8
GANAB 1
LRP5
PRKCSH
SEC63
SEC61B 2		ADPLD (OMIM PS174050)ADFew cysts occasionally reportedPolycystic liver disease
MUC1ADTKD-MUC1 (previously known as MCKD1)ADTubulointerstitial disease; few small corticomedullary cysts in 50%; normal or small-sized kidneys; CKD, highly variable progression to ESRDHyperuricemia, gout
RENADTKD-REN (previously known as FJHN2)ADTubulointerstitial disease, cysts, slowly progressive CKDAnemia, hyperuricemia, gout
SEC61A1ADTKD-SEC61A1 3 (also referred to as FJHN4)ADBilateral small cysts in 50%; normal or small-sized kidneys; CKDIUGR, congenital anemia
UMODADTKD-UMOD (previously known as FJHN1 or MCKD2)ADTubulointerstitial disease; normal or small kidneys; few unilateral or bilateral cysts in 1/3; variable progression of CKD to ESRDHyperuricemia, gout
JAG1
NOTCH2		Alagille syndromeADRenal dysplasia