Balkan Journal of Medical Genetics

PHENOTYPIC VARIABILITY OF 17Q12 MICRODELETION SYNDROME – THREE CASES AND REVIEW OF LITERATURE
Țuțulan-Cuniță A, Pavel AG, Dimos L, Nedelea M, Ursuleanu A, Neacșu AT, Budișteanu M, Stambouli D
*Corresponding Author: Andreea Țuțulan-Cuniță, Cytogenomic Medical Laboratory, 35 Calea Floreasca, Bucharest, 14453, Romania, Tel: 0040212331354, Fax: 0040212331357, E-mail: cunita@cytogenomic.ro
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INTRODUCTION

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, 4-7]. 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 HFN1B gene [1]. 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 HFN1B and LHX1 are hypothesized to be essential for renal function, neuropsychiatric conditions, and female genital anomalies [2, 8]. Many of the remaining genes, such as CCL and TBC1D, have multiple copies as normal population variants and are not likely to be dosage sensitive. Reciprocal duplications are associated with intellectual disability and epilepsy, though asymptomatic individuals have also been described [1]. 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 et al. (2019) [9] found that 4.2% of fetuses carried a 17q12 deletions spanning between 1.42-1.58 Mb in a cohort of 126 pregnancies with renal anomalies detected by ultrasound. 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.

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