Chromosome 17q12 microdeletion syndrome (MIM 614527) is a contiguous gene deletion syndrome caused by a 1–2.5 Mb loss [1, 2, 3], with a widely variable phenotype ranging from prenatal multicystic dysplastic kidneys or other urinary system anomalies to postnatal pancreatic disfunction (maturity onset diabetes of the young type 5 – MODY5) in approx. 40% of patients, or neurodevelopmental disorder (mild to moderate intellectual disability, speech delay, autistic features, schizophrenia, rarely epilepsy) in approx. 50% of patients [1, 3]. Facial dysmorphisms (frontal bossing, malar flattening, micrognathia, retrognathia, downslanting palpebral fissures, depressed nasal bridge) have been described, as well as pancreatic atrophy, liver abnormalities, genital anomalies in both sexes or Mullerian dysplasia or aplasia in females, transient neonatal hypercalcemia, and neonatal cholestasis [1–2, 4,5,6,7]. The same genetic defect has been associated with Mayer-Rokitansky-Kuester-Hauser syndrome, suggesting the existence of a continuous spectrum of phenotypes associated with 17q12 microdeletion [5]. However, to date, no correlation between the deletion size and gene content and clinical phenotype has been established. Moreover, patients with similar phenotypes were reported, carrying mutations in
Deletion of 17q12 is incompletely penetrant and its expressivity is highly variable, ranging from severe anomalies, leading to kidney failure before birth, to mild or no problems at all. While 70% of deletions occur de novo, instances where the deletion was inherited from an asymptomatic parent have been reported [6].
The critical region at 17q12 is flanked by polymorphic segmental duplications and contains at least 15 genes, out of which
While the overall prevalence of 17q12 deletion syndrome is unknown, a Danish study estimated its country prevalence as 1.6:1,000,000 [7]. Wan
In this article, we present 3 new cases of 17q12 deletions and review a large number of the reports, covering 92 patients with this genetic anomaly. Patients were selected based on their renal disorder phenotype or, if asymptomatic and carrying the deletion, the presence of a renal phenotype in a first degree relative. Patients with a primary diagnosis of Mullerian dysplasia or aplasia, Mayer-Rokitansky-Kuester-Hauser syndrome or only MODY5 were not included in the current study. However, given the complexity and the wide variability of the phenotype, from asymptomatic to lethal, the genetic counseling is therefore difficult and conversations about the implications of 17q12 microdeletion must continue.
Patient A was a 19-year-old gravida 1, referred for genetic testing at 24 weeks. She was selected due to a unilateral multicystic dysplastic kidney of the fetus, without other anomalies and with a normal fetal growth. The results of the biochemical screening for chromosomal aneuploidies were not available.
Patient B was a 26-year-old gravida 1, referred for genetic testing at 17 weeks. She was selected due to megabladder (defined as the sagittal dimension of the bladder (mm) greater than gestational age (weeks) plus 12), single umbilical artery, choroid plexus cyst, and possibly absent ductus arteriosus. First trimester biochemical screening results showed a high risk for chromosomal aneuploidies (1/56 for trisomy 21, 1/107 for trisomy 13, and 1/193 for trisomy 18; cutoff 1/250). In both cases, amniotic fluid was collected for analysis.
Patient C was a 7 year 5 months old boy, referred to genetic investigations following a diagnosis of autism spectrum disorder with developmental delay. He is the second child of healthy, nonconsanguineous parents born at 39 weeks, after a normal pregnancy, except for an ultrasound image of hydronephrosis in the right kidney at 22 weeks of gestation. With a birth weight of 2,850 g, a length of 52 cm, and an Apgar score of 7 due to some breathing difficulties, the patient had good postnatal adaptation. His developmental landmarks were delayed (he held his head at 7 months, sat at 12 months, walked at 1 year and 7 months, and pronounced first syllables at 1 year and 8 months, with his first words at 5 years). Hydronephrosis was surgically corrected at 12 months. He was diagnosed with autism spectrum disorder (ASD) at 3 years and started applied behavior analysis (ABA) therapy as well as speech therapy and cognitive stimulation at the age of 4. Currently, he attends his final year of kindergarten, with satisfactory results, though with socialization difficulties. The family history revealed the presence of a maternal cousin with cognitive delay and epilepsy. Clinical evaluation showed macrocephaly (occipitofrontal circumference 58 cm, +4.3 SD), dysmorphic facial features (deep set eyes, synophris, long philtrum, anteverted nostrils, posteriorely rotated ears, abnormal teeth, micrognathia); prominent occiput; joint hyperlaxity, single palmar crease, spindle-shaped fingers, clinodactily of the fifth finger; inverted nipples; small phallus and bilateral cryptorchidism; hirsutism; poor fine and gross motor skills, hypotonia, language and speech problems (poor language production, inability to understand complex orders, echolalia, polymorphic dyslalia); mild intellectual disability (IQ 60); social skills deficit with poor eye contact, difficulties in interaction with other persons, stereotyped behavior, low tolerance to frustration. An MRI investigation showed a mild bilateral frontal atrophy and a small frontobasal subarachnoidian cyst.
Genetic counselling of the patients was done by a clinical geneticist. Written informed consent on the use of their data for scientific purposes was given by the patients (A, B) or patient's legal guardian (C). Array-CGH was performed on an Agilent Technologies 60K platform according to the supplied protocol for patients A and B, while SNP array (Affymetrix) on a 750K platform was carried out for C patient. Following genetic analysis, pregnancies of patients A and B were terminated, without pursuing any further investigations.
Written informed consent on the use of their data for scientific purposes was given by all patients, in compliance with international and national regulations. Patient C was investigated within the frame of research project EEA RO-NO 6/2019, in accordance with the above regulations and approved by the institutional Ethics Committee, no. 33/Nov. 26, 2019.
The fetus of patient A carried a microdeletion with a minimal size of 1.35 Mb at 17q12, 34,817,422-36,168,104 (hg19), encompassing 18 genes:
Patient C presented a 1.80 Mb deletion at 17q12 at 34,475,679-36,283,807 (hg19) including
In neither case was parental DNA available for further investigation.
While the number of reported prenatal cases of 17q12 microdeletion is increasing and its clinical description is continuously updated, the phenotypic variability of this syndrome and the difficulties it raises in genetic counselling invite a broader discussion regarding the molecular mechanisms underlying this condition and their correlation with clinical presentations. Decramer
Our report describes three cases with prenatal urinary tract anomalies (multicystic dysplastic kidney, megabladder, and hydronephrosis, respectively); two of the pregnancies were subsequently terminated, while the third case had developmental delay and ASD. All our patients carry only one functional copy of four genes classified as pathogenic in OMIM:
As illustrated in Table 1, prenatal phenotypes associated with 17q12 microdeletion cover a large spectrum of ultrasound markers, from none to hyperechogenic, multicystic, or enlarged kidneys, absent unilateral kidney, and hydronephrosis. These markers can be detected at as early as 15 weeks of gestation [35], along with other findings (intestinal obstruction, congenital diaphragmatic hernia, lung anomalies, persistent left superior vena cava, poly- or oligohydramnios etc.). Two of our cases fall within the beginning of this spectrum, with single urinary tract abnormalities and with normal fetal growth. It is estimated that prenatal renal cysts are detected in more than half of the patients with post-natal kidney anomalies and that, regardless cyst detection in utero, most patients develop or increase their number in the first year of life [10]. Our reviewed cases include two sets of twins (P30–31, P44–45) carrying identical deletions. P30–31 twins exhibited similar prenatal phenotypes while progressing discordantly following birth, some patients presented prenatal kidney abnormalities which resolved after birth, while others did not show any anomaly upon prenatal ultrasound, but postnatal developmental delay and neuropsychiatric symptoms (Table 1). Moreover, the reviewed literature describes patients with mild phenotypes, who were diagnosed with 17q12 microdeletion syndrome only after having an affected pregnancy or due to other primary complains such as hypomagnesemia and subsequent investigations leading to renal disorder (e.g. P92 – Table 1). Difficulties in reviewing medical records and attaining an accurate medical history, particularly in adult and elder patients, make, however, statistics ultimately unreliable.
Clinical data of the patients and reviewed cases.
1. | Fetus# |
1.42 Mb |
HN | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 9 |
2. | Fetus |
1.48 Mb |
Left MCDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | C | 13 |
3. | Fetus# |
1.58 Mb |
bDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 9 |
4. | Fetus |
1.58 Mb |
Right MCDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | C | 13 |
5. | Fetus# |
1.59 Mb |
bHK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 14 |
6. | Fetus# |
1.74 Mb |
bMDK UTA | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 |
7. | Fetus# |
1.32 Mb |
UTA | - | + | - | - | - | - | - | - | - | - | - | - | - | - | - | Patient B current study |
8. | Fetus, male# |
1.75 Mb |
bHK, bHN, UTA (18 wks) |
- | - | - | - | - | - | - | - | - | - | - | - | - | - | + C | 15 |
9. | Fetus, female§ |
1.39 Mb |
bHK (at 19 wks) |
+ | + | - | - | - | - | - | - | - | - | - | - | - | - | - | 16 |
10. | Fetus# |
1.57 Mb |
bHK (22 weeks) | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 17 |
11. | Fetus, male# |
n/a |
bHK, bDK, one cyst | - | + | - | - | - | - | - | - | - | - | - | - | - | - | + C | 7 |
12. | Fetus# |
1.58 Mb |
HK, MDK | - | - | - | - | -‘ | - | - | - | - | - | - | - | - | - | - | 18 |
13. | Fetus |
1.58 Mb |
HK, bHN | - | - | - | - | -‘ | - | - | - | - | - | - | - | - | - | - | 18 |
14. | Fetus# |
1.60 Mb |
HK, bDK | - | - | - | - | -‘ | - | - | - | - | - | - | - | - | - | - | 18 |
15. | Fetus |
1.94 Mb |
HK, left MCDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
16. | Fetus# |
1.35 Mb |
MDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | Patient A current study |
17. | Fetus |
1.42 Mb |
HK, MDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | + C | 18 |
18. | Fetus |
1.42 Mb |
HK | - | - | PHA | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
19. | Fetus |
1.49 Mb |
left HK, right MCDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
20. | Fetus# |
1.60 Mb |
bMCDK, bilateral cystic adenomatoid malformation | - | + | AHA | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
21. | Fetus |
1,49 Mb |
HK | - | - | PHA | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
22. | Fetus |
1.58 Mb |
HMDK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
23. | Fetus, male# |
1.93 Mb |
bHMDK | - | + | PHA | - | - | - | - | - | - | - | - | - | - | - | - | 19 |
24. | Fetus# |
1.93 Mb |
bHMDK | - | - | PHA | - | - | - | - | - | - | - | - | - | - | - | - | 18 |
25. | Fetus, female# |
n/a |
bHK | - | - | - | - | - | - | - | - | - | - | - | - | - | - | + | 7 |
26. | n/a§ |
1.58 Mb |
HK | - | - | - | - | - | - | + | - | - | - | - | - | - | - | - | 9 |
27. | Male |
n/a |
- | - | + | OHA | bMCK | + | - | - | - | - | - | - | - | - | - | + C | 7 |
28. | Female |
1.49 Mb |
HK | + | + | PHA | - | - | + | + | + | - | - | - | - | - | - | - | 20 |
29. | Male |
1.43 Mb |
MK | - | - | OHA | MK | + | - | - | + | - | - | + | + | - | - | - | 2 |
30. | Male |
1.59 Mb |
bHK |
+ | + | PHA | HMK |
+ | - | - | - | - | - | - | - | - | - | + C | 20 |
31. | Male |
1.59 Mb |
bHK |
- | - | - | bHMK |
+ | - | - | - | - | - | - | - | - | - | + C | 20 |
32. | n/a |
1.48 Mb |
RPS | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 9 |
33. | Male |
1.69 Mb |
bMK | - | + | - | bMK | + | - | + | - | - | - | + | - | + | + | + C | 4 |
34. | Male |
1.60 Mb |
HK | - | - | PHA | MK | + | - | - | - | - | - | - | - | - | - | + C | 21 |
35. | Male |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | + C | 12 |
36. | Female |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
37. | n/a |
1.58 Mb |
MCK | - | - | - | MDK | + | - | - | - | + | - | - | - | - | - | - | 9 |
38. | Female |
n/a |
- | - | - | PHA | - | + | - | + | - | + | - | - | + | + | + | + C | 7 |
39. | Male |
1.40 Mb |
different size kidneys (30 wks) | - | - | - | bHMDK | + | - | - | - | + | - | - | - | - | - | + C | 22 |
40. | Male |
1,84 Mb |
CK | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 23 | |
41. | Male |
1,50 Mb |
HK | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 23 |
42. | n/a |
1.40 Mb |
HK (33 weeks) | - | - | - | MK |
- | - | - | - | + | + | + | - | - | - | + C | 17 |
43. | n/a |
1.70 Mb |
HK (23 weeks) | - | - | - | MK |
- | - | - | - | + | - | - | - | - | - | + C | 17 |
44. | Female |
1.57 Mb |
HK | - | - | - | HMCK | - | - | - | - | + | - | - | - | - | - | - | 17 |
45. | Female |
1.57 Mb |
HK | - | - | - | HMCK | - | - | - | - | + | - | - | - | - | - | - | 17 |
46. | Female |
1.79 Mb |
absent left kidney | - | + | PHA | HMDK | + | - | + | - | + | - | - | - | + | - | + C | 24 |
47. | Male |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
48. | Male |
2.07 Mb |
MK | - | - | - | MK /HK | + | - | - | - | + | + | - | + | + | + | - | 4 |
49. | Female |
1.75 Mb |
- | - | - | - | bDK | - | - | - | - | - | - | - | - | - | - | C | 15 |
50. | Male |
1.43 Mb |
MDK | - | - | - | MDK |
+ | - | - | - | - | - | + | - | - | - | - | 2 |
51. | Male |
1.88 Mb |
bHK (15 wks) |
+ | - | - | HMK |
- | + | + | + | - | - | + | - | + | - | - | 25 |
52. | Female |
n/a |
- | - | - | - | - | - | - | - | - | + | - | - | - | + | - | + C | 7 |
53. | Male |
n/a |
- | - | - | - | AG | + | + | - | - | + | + | - | - | - | + | - | 26 |
54. | Female |
1.40 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | + C | 22 |
55. | Male |
n/a |
- | - | - | - | One cyst, partial duplicated collecting system | + | + | + | + | + | + | + | - | 7 | |||
56. | Male |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
57. | Male |
1.80 Mb |
HN (22 weeks) | - | - | - | - | + | - | - | - | + | - | - | - | + | - | - | Patient C current study |
58. | Male |
n/a |
- | - | + | - | - | + | - | - | + | + | - | - | - | + | - | - | 27 |
59. | Male |
1.83 Mb |
HK, MCK, PY, HY | - | - | - | moderate renal failure | - | - | + | - | + | - | - | - | - | - | - | 23 |
60. | Female |
n/a |
- | - | - | - | - | + | - | - | - | + | - | - | - | + | - | + C | 7 |
61. | Male |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
62. | Male |
1.78 Mb |
bHMK | - | - | - | LK | - | - | - | - | + | - | - | - | + | - | + C | 21 |
63. | Female |
n/a |
- | - | + | - | - | + | - | + | - | + | - | - | - | + | + | + | 27 |
64. | Female |
1.73 Mb |
bHMK | - | - | - | MK | - | - | - | - | + | - | - | - | - | - | + | 4 |
65. | Male |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
66. | Male |
1.43 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | + | - | - | 5 |
67. | Female |
1,43 Mb |
MK | - | - | - | - | + | - | - | - | + | - | - | - | - | - | + | 2 |
68. | Female |
n/a |
MCK | - | - | PHA | left AG | - | - | - | - | + | - | - | - | - | + | - | 7 |
69. | Male |
1.42 Mb |
- | - | - | - | bMCK | + | - | - | - | + | - | - | - | + | + | - | 27 |
70. | Male |
1.89 Mb |
- | - | - | - | - | + | - | - | + | + | - | + | - | - | + | - | 28 |
71. | Female |
1.42 Mb |
- | - | - | - | bMCK | - | - | - | - | - | - | - | - | - | O, D | + | 27 |
72. | Female |
1.50 Mb |
- | - | - | - | MCD | - | - | + | - | + | - | - | - | - | - | - | 29 |
73. | Female |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
74. | Female |
1,43 Mb |
- | - | - | - | DK |
- | - | - | - | + | - | - | - | - | + | - | 2 |
75. | Male |
1.40 Mb |
- | - | - | - | UVJO | - | - | + | - | + | - | - | - | - | D, Mg↓ | - | 30 |
76. | Female |
1.69 Mb |
left MCDK | - | - | - | involution of left |
- | - | - | - | - | - | - | - | - | - | + | 4 |
77. | Male |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
78. | Female |
1.58 Mb |
MCK | - | - | - | - | - | - | + | - | + | - | - | - | - | D | - | 31 |
79. | Male |
n/a |
- | - | - | - | bHK | + | - | + | - | + | - | + | - | + | O | + C | 7 |
80. | Female |
1.42 Mb |
HK | - | - | - | bMCK | - | - | - | - | - | - | - | - | - | - | + C | 18 |
81. | Female |
1.80 Mb |
- | - | - | - | bMCK, AF | + | - | + | - | + | - | - | - | - | - | + | 27 |
82. | Female |
1.78 Mb |
bHMK | - | - | - | one cyst | - | - | - | - | + | - | - | - | + | - | + C | 21 |
83. | Female |
n/a |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | D | + C | 7 |
84. | Female |
n/a |
- | - | - | - | bHY, bNP | - | - | + | - | + | - | - | - | - | - | + | 7 |
85. | Female |
1.59 Mb |
- | - | - | PHA | bMK | - | - | + | - | - | - | - | - | - | O, D | + C | 21 |
86. | Female |
1.58 Mb |
- | - | - | - | MCK | - | - | + | - | - | - | - | - | + | + | + C | 32 |
87. | Female |
1.58 Mb |
- | - | - | - | MCK |
- | - | + | - | + | - | - | - | + | D | - | 31 |
88. | Female |
1.38 Mb |
- | - | - | - | - | - | - | - | - | + | - | - | - | - | - | - | 12 |
89. | Female |
n/a |
- | - | - | - | HY | - | - | - | - | + | - | - | - | - | - | + C | 7 |
90. | Male |
n/a |
- | - | - | - | HN, UPJO | - | - | + | + | + | - | + | - | - | + |
- | 33 |
91. | Female |
n/a |
- | - | - | - | a/hypoplasia, AF | - | - | - | + | - | - | + | + | - | O, D | - | 27 |
92. | Male |
1,41 Mb |
- | - | - | - | bMCK | - | - | - | + | + | - | + | - | - | Mg↓, D | + | 34 |
TOTAL | 1.32–2.07 Mb |
56/92 (60.9%) | 4/92 (4.3%) | 12/92 (13.0%) | 14/92 (15.2%) | 32/75 (42.7%) | 23/75 (30.7%) | 4/75 (5.3%) | 18/75 (24%) | 8/75 (10.7%) | 49/75 (65.3%) | 3/75 (4%) | 11/75 (14.7%) | 4/75 (5.3%) | 18/75 (24%) | 21/75 (28%) | 34/75 (45.3%) |
AF – affected renal function; AG – agenesia; AHA – anhydramnios; b – bilateral; C – genetically confirmed; D – diabetes; DD – developmental delay; DF – dysmorphic features; DH – diaphragmatic hernia; DK - dysplastic kidney; DM – diabetes mellitus; HK – hyperechogenic kidney; HMK – hyperechogenic multicystic kidney; HMDK – hyperechogenic multicystic dysplastic kidney; HMK – hyperechogenic multicystic kidney; HN – hydronephrosis; HY – renal hypoplasia; ID – intellectual disability; LBW – low birth weight; LK – lobulated kidney; LOFC – low occipitofrontal circumference; MCK – multicystic kidney; MDK - multicystic dysplastic kidney; NP – nephropathy; NT - nuchal fold thickness; O – ocular anomalies; OHA – oligohydramnios; PCD – pelvicalyceal dilatation; PD – pelvic dilatation; PHA – polyhydramnios; PY – pyelectasis; RPS – renal pelvis separation; UPJO – ureteropelvic junction obstruction; UTA – urinary tract anomalies; UVJO - ureterovesical junction obstruction;
-pregnancy terminated;
- died after birth;
- death at a later age.
Among the reviewed patients, 42.7% had kidney anomalies, at least 30.7% exhibited some degree of developmental delay, and 65.3% had neuropsychiatric features such as autism, intellectual disability of variable severity, or attention deficit. Thus, the neuropsychiatric phenotypes appear to be more frequent among the patients with 17q12 microdeletion than renal disorder. Among other phenotypes described in these patients were fetal diaphragmatic hernia (4.3%) and amniotic fluid anomalies (polyhydramnios 12%; oligohydramnios 2.1%; anhydramnios 1.1%) in prenatal cases, and in postnatal cases, digestive tract anomalies, particularly related to liver and pancreas (24%), cardiovascular anomalies (10.7%), skeletal anomalies (14.7%), facial dysmorphisms (24%). Ocular anomalies, diabetes, and hypomagnesemia were also described, albeit rarely. The broad spectrum of observed phenotypes emphasizes, once more, the high variability of this syndrome, adding to a 34.4% incomplete penetrance estimated in the case of this deletion [36].
For 45.3% of the cases, family history included potentially related phenotypes, though with only 37.3% being genetically confirmed. 10 out of 92 patients inherited the microdeletion from either a mildly affected or an affected parent, while 4 out of 92 inherited it from an asymptomatic parent. Although dedicated databases such as DECIPHER and CNV Morbidity Map of Developmental Delay list large numbers of cases with this genetic aberration, two deletions are also found in the Control section of the last morbidity map (Figure 1), proving, in accordance with Mefford
The third patient had ASD as a main feature, in association with mild developmental delay, dysmorphic features and prenatal hydronephrosis. ASD has been previously reported in patients with 17q12 deletion, e.g., Vasileiou
Kaman
In conclusion, we bring further evidence for the genetic and morpho-physiological complexity of the 17q12 deletion syndrome, and report a novel, atypical clinical phenotype (patient B), with megabladder, single umbilical artery and choroid plexus cyst, not yet described in fetuses with 17q12 deletion. However, whole gene deletion of