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Mark P.R.,Spectrum Health | Radlinski B.C.,Michigan State University | Core N.,French National Center for Scientific Research | Fryer A.,Countess of Chester Hospital NHS Foundation Trust | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Interstitial deletions of 18q lead to a number of phenotypic features, including multiple types of foot deformities. Many of these associated phenotypes have had their critical regions narrowly defined. Here we report on three patients with small overlapping deletions of chromosome 18q determined by microarray analysis (chr18:72493281-73512553 hg19 coordinates). All of the patients have congenital vertical talus (CVT). Based on these findings and previous reports in the literature and databases, we narrow the critical region for CVT to a minimum of five genes (ZNF407, ZADH2, TSHZ1, C18orf62, and ZNF516), and propose that TSHZ1 is the likely causative gene for CVT in 18q deletion syndrome. © 2012 Wiley Periodicals, Inc.

Haldeman-Englert C.R.,Section on Medical Genetics
American Journal of Medical Genetics, Part A | Year: 2012

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue condition with clinical features that may include ocular hypertelorism, cleft palate, craniosynostosis, and vascular dilation and tortuosity. Here we describe a patient with LDS confirmed by genetic analysis (R528H mutation of TGFBR2) who presented at 3 months of age in respiratory distress of unknown origin. In addition to expressing several of the classic findings of LDS, including a novel finding of squamosal suture craniosynostosis, CT angiography revealed aortic dilation at the sinus of valsalva, pulmonary artery dilation that extrinsically compressed the right mainstem bronchus causing bronchomalacia, and an apical herniation of the right lung. This is the first documentation of concomitant airway and pulmonary findings in a patient with LDS. We suggest that (1) vascular abnormalities be considered as a cause of unexplained respiratory distress in a patient with LDS, and (2) pediatric patients exhibiting any of the physical findings listed above be evaluated for LDS with particular attention paid to vascular, airway, and/or pulmonary malformations. © 2012 Wiley Periodicals, Inc.

Tuz K.,Albany Medical College | Bachmann-Gagescu R.,University of Zurich | O'Day D.R.,University of Washington | Hua K.,Albany Medical College | And 25 more authors.
American Journal of Human Genetics | Year: 2014

Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown. © 2014 The American Society of Human Genetics.

Chong J.X.,University of Washington | McMillin M.J.,University of Washington | Shively K.M.,University of Washington | Beck A.E.,University of Washington | And 34 more authors.
American Journal of Human Genetics | Year: 2015

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s). © 2015 The American Society of Human Genetics.

Basel-Vanagaite L.,Raphael Recanati Genetic Institute | Basel-Vanagaite L.,Tel Aviv University | Yilmaz R.,University of Ulm | Tang S.,Ambry Genetics | And 17 more authors.
Human Genetics | Year: 2014

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis- intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new" syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome". © 2014 Springer-Verlag.

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