Variable phenotype in 17q12 microdeletions: Clinical and molecular characterization of a new case

Abstract

Microdeletions of 17q12 including the hepatocyte nuclear factor 1 beta (HNF1B) gene, as well as point mutations of this gene, are associated with the Renal Cysts and Diabetes syndrome (RCAD, OMIM 137920) and genitourinary alterations. Also, microdeletions encompassing HNF1B were identified as a cause of Mayer-RokitanskyKüster-Hauser Syndrome (MRKH, OMIM 277000) in females and, recently, were associated with intellectual disability, autistic features, cerebral anomaly and facial dysmorphisms. In this report, we describe a boy with a deletion in 17q12 region detected by SNP array, encompassing the HNF1B gene, that showed dysmorphic features, intellectual disability (ID), serious speech delay and autistic features. In addition, obesity was observed. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and his parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. Our case confirms the incomplete penetrance and variable expressivity of this deletion, its complex clinical variability, and strengthens the evidence that ID and stereotyped behaviors may be part of the phenotypic spectrum characterizing the affected patients. Also, it is useful to further delineate the phenotypes associated to the deletion being the first case in which obesity has been documented. We present a genotype-phenotype correlation discussing the possible role of some genes, encompassed by the deletion, in the etiology of the observed phenotypes.

Exploring the genetic basis of early-onset chronic kidney disease

“…different degrees of severity and/or organ involvement occur in different affected individuals that carry identical mutated alleles). An example of an autosomal dominant kidney disease with variable expressivity is given by HNF1B mutations that cause CAKUT, CKD and maturity-onset diabetes of the young (MODY) with variable age of onset and variable presence of MODY diabetes 24,25 . Variable expressivity mainly describes a complex genotype-phenotype relationship in dominant diseases.…”

Clinical Report of a 17q12 Microdeletion with Additionally Unreported Clinical Features

“…The only gene contained within our proband's deletion but not within the other deletions reported in the literature prior to the recent Palumbo et al case [13] was TBC1D3B . Other members of the TBC1 domain family including TBC1D3C , TBC1D3F , TBC1D3G , and TBC1D3H are included in our proband's deletion and in deletions described in other case reports [2, 3].…”

“…Recently, Palumbo et al [13] described a boy with a 17q12 deletion involving the CCL4L2 , TBC1D3H , TBC1D3G , ZNHIT3 , MYO19 , PIGW , DHRS11 , MRM , LHX1 , AATF , ACACA , TADA2A , DUSP14 , SYNRG , and HNF1B genes presenting with repetitive and compulsive-like behaviors, attention-deficit hyperactivity disorder, intellectual disability, language disabilities, and dysmorphic features including right posterior plagiocephaly, facial asymmetry, narrow forehead, hypotelorism, wide and fleshy auricular pavilions, protruding cheekbones, long philtrum, thin upper lip, tuft of hair on the neck, and clinodactyly of the fifth fingers [13]. …”

22q and two: 22q11.2 deletion syndrome and coexisting conditions

“…The severity among the patients can be variable (Mefford et al, 2007). Additional features associated with the 17q12 deletion syndrome (OMIM #614527) include pancreatic abnormalities, facial dysmorphism, genitourinary differences (including uterus didelphys and cryptorchidism), as well as cognitive and developmental differences (Loirat et al, 2010; Moreno-De-Luca et al, 2010; Palumbo et al, 2014). …”