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TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation.
Lemattre, C, Thevenon, J, Duffourd, Y, Nambot, S, Haquet, E, Vuadelle, B, Genevieve, D, Sarda, P, Bruel, AL, Kuentz, P, et al
American journal of medical genetics. Part A. 2018;(12):2813-2818
Abstract
Pierpont syndrome is a rare and sporadic syndrome, including developmental delay, facial characteristics, and abnormal extremities. Recently, a recurrent de novo TBL1XR1 variant (c.1337A > G; p.Tyr446Cys) has been identified in eight patients by whole-exome sequencing. A dominant-negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype. We report two patients with typical Pierpont-like syndrome features. Exome sequencing allowed identifying a de novo heterozygous missense TBL1XR1 variant in both patients, different from those already reported: p.Cys325Tyr and p.Tyr446His. The localization of these mutations and clinical features of Pierpont-like syndrome suggest that their functional consequences are comparable with the recurrent mutation previously described, and provided additional data to understand molecular mechanisms of TBL1XR1 anomalies.
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2.
Microphthalmia is not a mandatory finding in X-linked recessive syndromic microphthalmia caused by the recurrent BCOR variant p.Pro85Leu.
Kraus, C, Uebe, S, Thiel, CT, Ekici, AB, Reis, A, Zweier, C
American journal of medical genetics. Part A. 2018;(12):2872-2876
Abstract
Mutations in BCOR cause X-linked dominant and X-linked recessive forms of syndromic microphthalmia. By exome sequencing, we identified the recurrent BCOR mutation p.Pro85Leu in two brothers and their unaffected mother. While the older brother's phenotype completely fits the described phenotypic spectrum of X-linked recessive BCOR-associated Lenz microphthalmia syndrome, the younger brother showed developmental delay, microcephaly, and skeletal anomalies, but not the key feature of microphthalmia. In contrast to the previously published families, our findings demonstrate a large variability of BCOR-associated, syndromic phenotypes, indicating incomplete penetrance of p.Pro85Leu with regards to microphthalmia in males.
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First evidence of Smith-Magenis syndrome in mother and daughter due to a novel RAI mutation.
Acquaviva, F, Sana, ME, Della Monica, M, Pinelli, M, Postorivo, D, Fontana, P, Falco, MT, Nardone, AM, Lonardo, F, Iascone, M, et al
American journal of medical genetics. Part A. 2017;(1):231-238
Abstract
Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age. No patients have been reported to have had offspring. We here describe a girl with developmental delay, mainly compromising the speech area, and her mother with mild intellectual disabilities and minor dysmorphic features. Both had sleep disturbance and attention deficit disorder, but no other atypical behaviors have been reported. In both, CGH-array analysis detected a 15q13.3 interstitial duplication, encompassing CHRNA7. However, the same duplication has been observed in several, apparently healthy, maternal relatives. We, thus, performed a whole exome sequencing analysis, which detected a frameshift mutation in RAI1, de novo in the mother, and transmitted to her daughter. No other family members carried this mutation. This is the first report of an SMS patient having offspring. Our experience confirms the importance of searching for alternative causative genetic mechanisms in case of confounding/inconclusive findings such as a CGH-array result of uncertain significance. © 2016 Wiley Periodicals, Inc.
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Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome.
Carlston, CM, O'Donnell-Luria, AH, Underhill, HR, Cummings, BB, Weisburd, B, Minikel, EV, Birnbaum, DP, , , Tvrdik, T, MacArthur, DG, et al
Human mutation. 2017;(5):517-523
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Abstract
The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a 6-year-old female patient with seizures, developmental delay, dysmorphic features, and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype fit, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Review of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including pathogenic variants) during hematopoietic clonal expansion can occur with aging in healthy individuals. We examined all ASXL1 truncating variants in the ExAC database and determined most are likely somatic. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like BOS have reduced penetrance, or the misclassification of potentially pathogenic variants.
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Darier disease, multiple bone cysts, and aniridia due to double de novo heterozygous mutations in ATP2A2 and PAX6.
Castori, M, Barboni, L, Duncan, PJ, Paradisi, M, Laino, L, De Bernardo, C, Robinson, DO, Grammatico, P
American journal of medical genetics. Part A. 2009;(8):1768-72
Abstract
Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in ATP2A2 and characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Rare patients are described with variable bone involvement, but this association has never been sufficiently emphasized. Aniridia is a developmental disorder of the eye due to heterozygous mutations in PAX6. DD and aniridia are Mendelian traits mapping on independent loci and have never been reported in association. Here, we describe a 14-year-old girl showing the unique combination of DD, multiple bone cysts, and bilateral aniridia. Molecular investigations demonstrated that such a complex phenotype is due to double de novo heterozygous mutations in ATP2A2 and PAX6. Review of the literature indicates that, in DD, bone cysts are true developmental abnormalities of the skeleton. This finding suggests a role for ATP2A2 in bone biology. More systematic studies are expected in order to estimate the true prevalence of bone cysts in DD and the relationship between skeletal changes and ATP2A2 perturbation.
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Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype.
Zweier, C, Horn, D, Kraus, C, Rauch, A
American journal of medical genetics. Part A. 2006;(8):869-72
Abstract
Mowat-Wilson syndrome is a recently delineated severe mental retardation, multiple congenital anomalies syndrome caused by dominant nonsense or frameshift mutations, deletions or translocations of the zinc finger homeobox 1B gene (ZFHX1B). We report on a patient with exceptional mild phenotype caused by a novel and unusual splice mutation in the 5'UTR. The aberrant transcript leads to usage of an alternative upstream start codon. The resulting protein differs from the wild-type only in the first 24 amino acids. The aberrant protein therefore contains all known functional domains, but might lack a so far unrecognized putative N-terminal acylation site, which is probably important for neuronal function and facial structures.
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Inappropriate tall stature and renal ectopy in a male patient with X-linked congenital adrenal hypoplasia due to a novel missense mutation in the DAX-1 gene.
Franzese, A, Brunetti-Pierri, N, Spagnuolo, MI, Spadaro, R, Giugliano, M, Mukai, T, Valerio, G
American journal of medical genetics. Part A. 2005;(1):72-4
Abstract
Mutations in DAX-1 gene cause congenital adrenal hypoplasia (AHC). We present a male patient affected by X-linked adrenal hypoplasia congenita due to a novel DAX-1 missense mutation. The mutation V287G affects the C-terminal end of the DAX-1 protein which plays an important role in functioning of the receptor. In addition, our patient presented an inappropriate tall stature and renal ectopy, which have not been described in AHC so far.