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Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations

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Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations G C A T T A C G G C A T genes Article Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations Agnieszka Stembalska 1,* , Małgorzata Rydzanicz 2 , Agnieszka Pollak 2, Grazyna Kostrzewa 2, Piotr Stawinski 2, Mateusz Biela 3 , Rafal Ploski 2 and Robert Smigiel 3,* 1 Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland 2 Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland; [email protected] (M.R.); [email protected] (A.P.); [email protected] (G.K.); [email protected] (P.S.); [email protected] (R.P.) 3 Department of Paediatrics, Division of Paediatric Propedeutics and Rare Disorders, Wroclaw Medical University, 51-618 Wroclaw, Poland; [email protected] * Correspondence: [email protected] (A.S.); [email protected] (R.S.) Abstract: Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that Citation: Stembalska, A.; Rydzanicz, diagnosed in the postnatal period. M.; Pollak, A.; Kostrzewa, G.; Stawinski, P.; Biela, M.; Ploski, R.; Keywords: TMEM67 gene; prenatal and postnatal diagnosis; genetic and phenotypic diagnosis; Smigiel, R. Prenatal Versus Postnatal Joubert syndrome; Meckel–Gruber syndrome Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations. Genes 2021, 12, 1078. https://doi.org/10.3390/ genes12071078 1. Introduction Renal cystic diseases are a group of malformations of the kidney that develop in fetal Academic Editors: Claude Ferec and life or occur after birth but may not be visible until adulthood. Renal cysts can be congenital Livia Garavelli or acquired, focal, multifocal, one-sided, or bilateral [1–3]. There are several classifications of renal cysts [1,2,4]. Congenital renal cystic disorders are a genetically heterogeneous group Received: 25 May 2021 and can be isolated pathologies or can be associated with other nephrological/urological dis- Accepted: 8 July 2021 orders (ureteropelvic and ureterovesical junction obstruction, ureterocoele, posterior urethral Published: 16 July 2021 valves, and prune-belly syndrome) as well as with systemic disorders (e.g., tuberous sclerosis, Von Hippel–Lindau syndrome, various ciliopathies) [2–5]. It is important to distinguish Publisher’s Note: MDPI stays neutral between genetic and non-genetic causes because of the high risk of recurrence in the case with regard to jurisdictional claims in of a genetic disorder. In cases associated with extrarenal anomalies, the risk of a genetic published maps and institutional affil- etiology is increased, while genetic pathology is rare in the case of solitary cysts with iations. normal renal parenchyma and in isolated unilateral multicystic dysplastic kidney or cystic dysplasia [1,3]. The prognosis of renal cysts depends on their etiology and coexisting multiple anoma- lies. The presence of additional defects or oligohydramnios (especially earlier-onset) may Copyright: © 2021 by the authors. increase the risk of intrauterine or postnatal death [2,4]. Licensee MDPI, Basel, Switzerland. We report two patients with a prenatal diagnosis of polycystic kidney disease with This article is an open access article TMEM67 mutations identified in a whole-exome sequencing (WES) study. In one of the distributed under the terms and presented patients, the phenotypic diagnosis made prenatally was different from that conditions of the Creative Commons made in the postnatal period. The first proband with TMEM67 mutations suffers from Attribution (CC BY) license (https:// polycystic kidney and brain anomalies, which prenatally were diagnosed as Meckel–Gruber creativecommons.org/licenses/by/ syndrome, but postnatally were clinically verified as Joubert syndrome. In the second 4.0/). Genes 2021, 12, 1078. https://doi.org/10.3390/genes12071078 https://www.mdpi.com/journal/genes Genes 2021, 12, 1078 2 of 7 Genes 2021, 12, x FOR PEER REVIEW 2 of 7 proband with TMEM67 mutations, Meckel–Gruber syndrome was correctly diagnosed prenatallyGruber syndrome, and confirmed but postnatally in an autopsy. were clinically verified as Joubert syndrome. In the sec- ond proband with TMEM67 mutations, Meckel–Gruber syndrome was correctly diag- 2.nosed Clinical prenatally Reports and confirmed in an autopsy. 2.1. Case #1 2. Clinical Reports The 32-year-old woman has been referred for genetic counseling in the second trimester2.1. Case #1 of her second pregnancy due to fetal polycystic kidneys, a suspicion of age- nesis ofThe the 32-year-old cerebellar woman vermis, has and been heart referred defect for (multiple genetic muscularcounseling defects in the second in the ventriculartri- septummester of without her second hemodynamic pregnancy due significance). to fetal polycystic In prenatal kidneys, screeninga suspicion in of theagenesis first trimester,of onlythe cerebellar fetal tricuspid vermis, regurgitation and heart defect was (multi observed.ple muscular Screenings defects for in fetalthe ventricular trisomies sep- in the first tum without hemodynamic significance). In prenatal screening in the first trimester, only trimester and echocardiography in the second trimester of pregnancy were normal. fetal tricuspid regurgitation was observed. Screenings for fetal trisomies in the first tri- The woman had a healthy son from another relationship; family history was negative. mester and echocardiography in the second trimester of pregnancy were normal. The prenatalThe woman genetic had diagnosisa healthy son was from performed another relationship; in the sixteenth family week history of thewas presentnega- preg- nancy.tive. The After prenatal a normal genetic result diagnosis of karyotype was perf andormed aCGH in the test, sixteenth whole-exome week of sequencingthe present (WES) waspregnancy. performed After due a normal to suspected result of Meckel–Gruberkaryotype and aCGH syndrome. test, whole-exome In the echocardiography sequencing in the(WES) third was trimester performed of pregnancydue to suspected (32 weeks), Meckel–Gruber multiple syndrome. muscular In defects the echocardiog- were observed in theraphy ventricular in the third septum trimester without of pregnancy hemodynamic (32 weeks), significance. multiple muscular defects were ob- servedThe in child the ventricular was born septum by cesarean without section hemodynamic at term significance. at 38 weeks with symptoms of birth asphyxiaThe child (neonatal was born parameters: by cesarean weight section 3100 at term g, lengthat 38 weeks 52 cm, with OFC symptoms 34 cm). of birth Respiratory failure,asphyxia perinatal (neonatal hypoxia, parameters: and weight muscular 3100 hypotonia g, length 52 were cm, OFC observed, 34 cm). andRespiratory polycystic fail- kidneys andure, ventricularperinatal hypoxia, septum and defects muscular were hypotonia confirmed. were observed, Brain imaging and polycystic (USG, CT)kidneys after birth showedand ventricular no changes; septum cerebellar defects were structures confirmed. were Brain described imaging as (USG, normal. CT) Noafter typical birth facial showed no changes; cerebellar structures were described as normal. No typical facial dys- dysmorphic features were recognized (Figure1). morphic features were recognized (Figure 1). FigureFigure 1.1. TheThe childchild withwith JoubertJoubert syndrome.syndrome. InIn thethe fifthfifth monthmonth of life, rotatory rotatory nystagmus nystagmus was was observed. observed. In Inaddition addition to nystag- to nystagmus, convergentmus, convergent strabismus strabismus and and mild mild visual visual impairment impairment have been been described described in an in oph- an ophthal- thalmological examination. In an electrophysiological examination of visual pathways, a mological examination. In an electrophysiological examination of visual pathways, a bilaterally symmetrical response with normal latency was observed. In MRI of the brain, bilaterally symmetrical response with normal latency was observed. In MRI of the brain, agenesis or significant hypoplasia of the cerebellar vermis with distortion of the lumen of agenesisthe fourth or chamber significant ventricle hypoplasia (“bat-wing ofthe fourth cerebellar ventricle”) vermis and elongation with distortion of the ofupper the lumen ofcerebellar the fourth peduncles chamber was ventricle observed. (“bat-wing The presence fourth of the ventricle”) molar tooth and sign elongation in an MRI study of the upper cerebellarchanged the peduncles diagnosis was from observed. Meckel–Gru Theber presence syndrome of to the Joubert molar syndrome. tooth sign in an MRI study changedIn the the first diagnosis year of life, from developmental Meckel–Gruber delaysyndrome and hypertension to Joubert with syndrome.secondary hyper- trophicIn the cardiomyopathy first year of life, were developmental additionally observed. delay and Despite hypertension rehabilitation, with secondary the child hyper- trophicdoes not cardiomyopathy sit up alone in the were fourteenth
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