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De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family

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De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family International Journal of Molecular Sciences Case Report De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family Laura Castilla-Vallmanya 1 , Semra Gürsoy 2, Özlem Giray-Bozkaya 3, Aina Prat-Planas 1 , Gemma Bullich 4, Leslie Matalonga 4,Mónica Centeno-Pla 1 , Raquel Rabionet 1 , Daniel Grinberg 1 , Susanna Balcells 1 and Roser Urreizti 1,*,† 1 IBUB, IRSJD, and CIBERER (ISCIII), Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; [email protected] (L.C.-V.); [email protected] (A.P.-P.); [email protected] (M.C.-P.); [email protected] (R.R.); [email protected] (D.G.); [email protected] (S.B.) 2 Department of Pediatric Genetics, Dr. Behcet Uz Children’s Hospital, Izmir 35210, Turkey; [email protected] 3 Department of Pediatric Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey; [email protected] 4 CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; [email protected] (G.B.); [email protected] (L.M.) * Correspondence: [email protected] † Current address: Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu and CIBERER, 08950 Barcelona, Spain. Abstract: We present a Turkish family with two cousins (OC15 and OC15b) affected with syndromic developmental delay, microcephaly, and trigonocephaly but with some phenotypic traits distinct between them. OC15 showed asymmetrical skeletal defects and syndactyly, while OC15b presented Citation: Castilla-Vallmanya, L.; with a more severe microcephaly and semilobal holoprosencephaly. All four progenitors were Gürsoy, S.; Giray-Bozkaya, Ö.; related and OC15 parents were consanguineous. Whole Exome Sequencing (WES) analysis was Prat-Planas, A.; Bullich, G.; performed on patient OC15 as a singleton and on the OC15b trio. Selected variants were validated by Matalonga, L.; Centeno-Pla, M.; Rabionet, R.; Grinberg, D.; Balcells, S.; Sanger sequencing. We did not identify any shared variant that could be associated with the disease. et al. De Novo PORCN and ZIC2 Instead, each patient presented a de novo heterozygous variant in a different gene. OC15 carried a Mutations in a Highly nonsense mutation (p.Arg95*) in PORCN, which is a gene responsible for Goltz-Gorlin syndrome, Consanguineous Family. Int. J. Mol. while OC15b carried an indel mutation in ZIC2 leading to the substitution of three residues by a Sci. 2021, 22, 1549. https://doi.org/ proline (p.His404_Ser406delinsPro). Autosomal dominant mutations in ZIC2 have been associated 10.3390/ijms22041549 with holoprosencephaly 5. Both variants are absent in the general population and are predicted to be pathogenic. These two de novo heterozygous variants identified in the two patients seem to explain Received: 8 January 2021 the major phenotypic alterations of each particular case, instead of a homozygous variant that would Accepted: 31 January 2021 be expected by the underlying consanguinity. Published: 4 February 2021 Keywords: neurodevelopmental disease; clinical genetics; whole exome sequencing; consanguinity; Publisher’s Note: MDPI stays neutral focal dermal hypoplasia; holoprosencephaly with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Case Description Here, we report two de novo mutations causing severe neurodevel- opmental delay in two first degree cousins from a highly consanguineous family of Turkish Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. origin (Figure1). This article is an open access article Patient 1 was a 10-year-old girl and single child of a healthy, consanguineous couple of distributed under the terms and Turkish origin. The family had a history of non-syndromic intellectual disability and deaf- conditions of the Creative Commons ness, with several affected individuals for each trait. Prenatally, the mother was hospitalized Attribution (CC BY) license (https:// for a urinary tract infection. There was no history of polyhydramnios/oligohydramnios or creativecommons.org/licenses/by/ maternal diabetes. Patient 1 was born at term by normal vaginal delivery and the birth 4.0/). was uneventful. Her birth weight and height were 3.1 kg (−0.53 SD) and 48 cm (−0.71 SD), Int. J. Mol. Sci. 2021, 22, 1549. https://doi.org/10.3390/ijms22041549 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 10 Int. J. Mol. Sci. 2021, 22, 1549 2 of 10 the birth was uneventful. Her birth weight and height were 3.1 kg (−0.53 SD) and 48 cm (−0.71 SD), respectively. Since birth, she presented with failure to thrive and neonatal hy- potonia. Additionally, congenital hip dislocation was detected. At the six months follow- respectively.up, her weight Since was birth, 4.5 kg she (−4.08 presented SD), withheight failure was 58.5 to thrive cm (− and3.07 neonatal SD), and hypotonia. head circumfer- Addi- tionally,ence was congenital 37.3 cm (− hip4 SD). dislocation She showed was detected. several craniofacial At the six months dysmorphologies, follow-up, her including weight wassevere 4.5 microcephaly, kg (−4.08 SD), heighttrigonocephaly was 58.5 cm(with (− 3.07prominent SD), and metopic head circumference ridge), facial wasasymmetry 37.3 cm, (and−4 SD).other She features showed, such several as low craniofacial hairline, dysmorphologies,hypoplastic orbital including ridges, up severe-slanting microcephaly, palpebral trigonocephalyfissures, strabismus, (with sparse prominent eyebrows, metopic prominent ridge), ears, facial gingival asymmetry, hyperplasia and other, and features,high pal- suchate (Figure as low 2 hairline, and Table hypoplastic 1). Ocular orbital examination ridges, up-slantingrevealed a minimal palpebral bilateral fissures, optic strabismus, disc hy- sparsepoplasia. eyebrows, Short neck, prominent sometimes ears, with gingival crusting hyperplasia, of the skin, andwas highalso observed. palate (Figure In addition,2 and Table1). Ocular examination revealed a minimal bilateral optic disc hypoplasia. Short she presented with radial head dislocation, hypoplasia of the right clavicle, widely spaced neck, sometimes with crusting of the skin, was also observed. In addition, she presented nipples, ulnar deviation of the fingers, and complete cutaneous syndactyly of the right with radial head dislocation, hypoplasia of the right clavicle, widely spaced nipples, ulnar 3rd and 4th fingers with bony fusion of the distal phalanges, overlapping toes on both deviation of the fingers, and complete cutaneous syndactyly of the right 3rd and 4th fingers feet, and spasticity of the lower limbs. She had thickened subcutaneous soft tissue on the with bony fusion of the distal phalanges, overlapping toes on both feet, and spasticity of proximal phalanges (prominently second finger) of the left hand. The patient had focal the lower limbs. She had thickened subcutaneous soft tissue on the proximal phalanges dermal hypoplasia in the left region of the neck, axillary region, and the middle region of (prominently second finger) of the left hand. The patient had focal dermal hypoplasia her right, lower limb. She had also hypo-hyperpigmented lesions in her back, pelvic re- in the left region of the neck, axillary region, and the middle region of her right, lower gion, and trunk (not shown). The patient also had hypodontia. Brain magnetic resonance limb. She had also hypo-hyperpigmented lesions in her back, pelvic region, and trunk imaging (MRI) revealed periventricular gliotic changes, thin corpus callosum, and mod- (not shown). The patient also had hypodontia. Brain magnetic resonance imaging (MRI) erate cerebellar atrophy. She was severely delayed (no head control at four years) and revealed periventricular gliotic changes, thin corpus callosum, and moderate cerebellar atrophy.suffered from She wasepilepsy. severely The delayedseizures, (nowhich head were control generally at four triggered years) by and fever, suffered were fromame- epilepsy.nable to Themultiple seizures, drug which regimens. were generallyShe passed triggered away at by the fever, age wereof 10 amenable due to a torespiratory multiple druginfection. regimens. She was She considered passed away compatible at the age with of Opitz 10 due C to clinical a respiratory spectrum. infection. Previous She genetic was consideredanalyses included compatible a normal with Opitzkaryotype C clinical and a spectrum. normal array Previous comparative genetic analyses genomic included hybridi- azat normalion (array karyotype CGH) and a normal array comparative genomic hybridization (array CGH). FigureFigure 1.1.Extended Extended familyfamily pedigreepedigree showingshowing thethe relationsrelations amongamong allall fourfour progenitors,progenitors, thethe twotwo mothersmothers beingbeing sisters,sisters,and and thethe two two fathers fathers being being cousins cousins once once removed. removed. Patient Patient 1’s parents1’s parents are also are cousinsalso cousins once removedonce removed (connected (connected through through a double a bond).double Patients bond). 1Patients and 2 in 1 black. and 2 Patient in black. 2’s microcephalicPatient 2’s microcep sister inhalic grey. sister Squared in grey. pattern: Squared congenital pattern: deafness. congenital Wavy deafness pattern:. intellectualWavy pattern: disability. intellectual disability. Int. J. Mol. Sci. 2021, 22, 1549 3 of 10 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 10 FigureFigure 2. Pictures 2. Pictures of
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