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Yilmaz R.,Institute of Human GeneticsUniversity of UlmUlmGermany | Price S.,NHS TrustNorthamptonUK | Kubisch C.,Institute of Human GeneticsUniversity Medical Center Hamburg EppendorfHamburgGermany | Clayton-Smith J.,Saint Marys University | Borck G.,Institute of Human GeneticsUniversity of UlmUlmGermany
American Journal of Medical Genetics, Part A | Year: 2015

Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-"mental retardation" syndromes and the more severe genitopatellar syndrome. The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome. © 2015 Wiley Periodicals, Inc. Source

Spielmann M.,Institute for Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Barbi G.,Institute of Human GeneticsUniversity of UlmUlmGermany | Flottmann R.,Institute for Medical and Human GeneticsCharite Universitatsmedizin BerlinBerlinGermany | Kehrer-Sawatzki H.,Institute of Human GeneticsUniversity of UlmUlmGermany | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2016

The femoral facial syndrome (FFS) is a rare congenital anomaly syndrome characterized by bilateral femoral hypoplasia and facial dysmorphism. The etiology of FFS is currently unknown but maternal/gestational diabetes has been proposed as a strong risk factor for syndromic femoral hypoplasia. In affected children born to non-diabetic mothers, a genetic contribution to FFS is suspected; however, no chromosomal anomalies or gene mutations have been identified so far. Here, we report on a girl with FFS and a de novo complex chromosome rearrangement of terminal chromosome 2q37.2. Radiographs of the pelvis and lower limbs showed bilateral shortening and bowing of the femur and radiographs of hands and feet revealed a brachydactyly type E (BDE). Using high resolution array-CGH, qPCR, and FISH, we detected a ∼1.9Mb duplication in the chromosomal region 2q37.2 and a ∼5.4Mb deletion on chromosome 2q37.3 that were absent in the parents. The duplication contains six genes and the deletion encompasses 68 genes; the latter has previously been shown to cause BDE (through haploinsufficiency for HDAC4) but not femoral hypoplasia. Therefore, we propose that the duplication 2q37.2 could be causative for the femur phenotype. To the best of our knowledge, our report is the first to propose a genetic cause in a case of FFS. © 2016 Wiley Periodicals, Inc. Source

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