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Reynolds B.C.,Renal Unit | Lemmers R.J.L.F.,Leiden University | Tolmie J.,Ferguson Smith Center | Howatson A.G.,Royal Hospital for Sick Children | Hughes D.A.,Renal Unit
Pediatric Nephrology | Year: 2010

We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats' disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome. © 2010 The Author(s).

Snape K.,Institute of Cancer Research | Hanks S.,Institute of Cancer Research | Ruark E.,Institute of Cancer Research | Barros-Nunez P.,Instituto Mexicano del Seguro Social | And 17 more authors.
Nature Genetics | Year: 2011

Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division. © 2011 Nature America, Inc. All rights reserved.

Le Goff C.,French Institute of Health and Medical Research | Mahaut C.,French Institute of Health and Medical Research | Abhyankar A.,Rockefeller University | Le Goff W.,University Pierre and Marie Curie | And 13 more authors.
Nature Genetics | Year: 2012

Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.

Joss S.,Yorkshire Regional Genetics Center | Joss S.,Ferguson Smith Center | Kini U.,Oxford Genetics | Fisher R.,Yorkshire Regional Genetics Center | And 4 more authors.
European Journal of Medical Genetics | Year: 2011

Ulnar Mammary syndrome (UMS) is an autosomal disorder caused by haploinsufficiency of the TBX3 gene. There is marked intrafamilial variation in expression of the syndrome. We present one three generation family in which the proband has absence of the right ulna and third, fourth and fifth rays in her right hand. Her mother and maternal grandmother have more subtle anomalies while all have a similar facial appearance with a broad nasal tip, a broad jaw, a prominent chin and a tongue frenulum. They have a single base pair insertion (c. 992dup) in TBX3. We compare faces from the handful of published UMS patients which include photographs, this family and four other cases with TBX3 mutations. All have similarities in appearance which we suggest could alert clinicians to the possibility of a TBX3 mutation if individuals present with more subtle features of UMS such as postaxial polydactyly, isolated 5th finger anomalies, delayed puberty in males, breast hypoplasia or short stature with or without growth hormone deficiency. © 2010 Elsevier Masson SAS.

Willemsen M.,Radboud University Nijmegen | Beunders G.,VU University Amsterdam | Callaghan M.,Ferguson Smith Center | de Leeuw N.,Radboud University Nijmegen | And 10 more authors.
Clinical Genetics | Year: 2011

The Kleefstra syndrome (Online Mendelian Inheritance in Man 607001) is caused by a submicroscopic 9q34.3 deletion or by intragenic euchromatin histone methyl transferase 1 (EHMT1) mutations. So far only de novo occurrence of mutations has been reported, whereas 9q34.3 deletions can be either de novo or caused by complex chromosomal rearrangements or translocations. Here we give the first descriptions of affected parent-to-child transmission of Kleefstra syndrome caused by small interstitial deletions, approximately 200 kb, involving part of the EHMT1 gene. Additional genome-wide array studies in the parents showed the presence of similar deletions in both mothers who only had mild learning difficulties and minor facial characteristics suggesting either variable clinical expression or somatic mosaicism for these deletions. Further studies showed only one of the maternal deletions resulted in significantly quantitative differences in signal intensity on the array between the mother and her child. But by investigating different tissues with additional fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) analyses, we confirmed somatic mosaicism in both mothers. Careful clinical and cytogenetic assessments of parents of an affected proband with an (interstitial) 9q34.3 microdeletion are merited for accurate estimation of recurrence risk. © 2011 John Wiley & Sons A/S.

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