Partial Deletion Of Ankrd11 Results In The Kbg Phenotype Distinct From The 16q24.3 Microdeletion Syndrome
16q24; 3; ANKRD11; ASD; autism; delineation; diagnostic-criteria; Genetics & Heredity; KBG; macrodontia; MCA; microdeletion; mosaicism; MR
KBG syndrome (OMIM 148050) is a very rare genetic disorder characterized by macrodontia, distinctive craniofacial abnormalities, short stature, intellectual disability, skeletal, and neurologic involvement. Approximately 60 patients have been reported since it was first described in 1975. Recently mutations in ANKRD11 have been documented in patients with KBG syndrome, and it has been proposed that haploinsufficiency of ANKRD11 is the cause of this syndrome. In addition, copy number variation in the 16q24.3 region that includes ANKRD11 results in a variable phenotype that overlaps with KBG syndrome and also includes autism spectrum disorders and other dysmorphic facial features. In this report we present a 21/2-year-old African American male with features highly suggestive of KBG syndrome. Genomic microarray identified an intragenic 154kb deletion at 16q24.3 within ANKRD11. This child's mother was mosaic for the same deletion (present in approximately 38% of cells) and exhibited a milder phenotype including macrodontia, short stature and brachydactyly. This family provides additional evidence that ANKRD11 causes KBG syndrome, and the mild phenotype in the mosaic form suggests that KBG phenotypes might be dose dependent, differentiating it from the more variable 16q24.3 microdeletion syndrome. This family has additional features that might expand the phenotype of KBG syndrome. (c) 2013 Wiley Periodicals, Inc.
Khalifa M; Stein J; Grau L; Nelson V; Meck J; Aradhya S; Duby J
American Journal of Medical Genetics Part A
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/ajmg.a.35739" target="_blank" rel="noreferrer noopener">10.1002/ajmg.a.35739</a>
Exome Sequencing Reveals A Novel Wdr45 Frameshift Mutation And Inherited Polr3a Heterozygous Variants In A Female With A Complex Phenotype And Mixed Brain Mri Findings
4H syndrome; accumulation; atp13a2 mutations; clinical spectrum; Demyelinating disease; diabetes-mellitus; gene; Genetics & Heredity; hallervorden-spatz-syndrome; hypogonadism; iron; Leukodystrophy; Leukodystrophy; NBIA; neurodegeneration; POLR3A; spastic paraplegia spg35; WDR45; Whole exome sequencing
WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A > G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A > T) and a paternally inherited variant (1745G > A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes. (C) 2015 Elsevier Masson SAS. All rights reserved.
Khalifa M; Naffaa L
European Journal of Medical Genetics
2015
2015-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.ejmg.2015.05.009" target="_blank" rel="noreferrer noopener">10.1016/j.ejmg.2015.05.009</a>
Exome Sequencing Identifies a Novel EP300 Frame Shift Mutation in a Patient With Features That Overlap Cornelia de Lange Syndrome
cbp; Cornelia de Lange syndrome; creb-binding protein; embryonic stem-cells; EP300; genetic-heterogeneity; Genetics & Heredity; MCA/ID; p300; Rubinstein-Taybi syndrome; Rubinstein-Taybi syndrome; transcriptional coactivators; whole exome sequencing
Rubinstein-Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS-related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS-related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted. (c) 2013 Wiley Periodicals, Inc.
Woods S A; Robinson H B; Kohler L J; Agamanolis D; Sterbenz G; Khalifa M
American Journal of Medical Genetics Part A
2014
2014-01
Journal Article
<a href="http://doi.org/10.1002/ajmg.a.36237" target="_blank" rel="noreferrer noopener">10.1002/ajmg.a.36237</a>