Center for Human Genetics Inc.

Cambridge, MA, United States

Center for Human Genetics Inc.

Cambridge, MA, United States

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Santen G.W.E.,Leiden University | Aten E.,Leiden University | Vulto-van Silfhout A.T.,Radboud University Nijmegen | Pottinger C.,Glan Clwyd Hospital | And 78 more authors.
Human Mutation | Year: 2013

De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation. © 2013 WILEY PERIODICALS, INC.


Uhlmann W.R.,University of Michigan | Penaherrera M.S.,University of British Columbia | Penaherrera M.S.,Child and Family Research Institute | Robinson W.P.,University of British Columbia | And 5 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin (HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD). The proband had biparental inheritance of HTT alleles (42/44 CAG repeats). Given the negative UPD results, the proband's unaffected mother either had a reduced penetrance allele that expanded into the full mutation range during transmission to our patient or an unknown full HTT mutation and died before symptom onset, unlikely given no family history of HD and asymptomatic at age 59. We made the novel observation in our literature review that most patients with biallelic HD did not have two full HTT mutations. Most had one HTT allele that was in the intermediate or reduced penetrance ranges or 40 CAG repeats, the lowest limit of the full mutation range. Although the number of patients is small, when an allele in these size ranges was present, generally the age of HD onset was in the 50s. If the second HTT allele had >45 repeats, then onset was typically 20s-30s. While similar ages of onset have been reported for patients with one or two HTT mutations, patients with biallelic mutations may have later onset if an expanded HTT allele has ≤40 CAG repeats. Finally, we propose that "biallelic mutations" or "compound heterozygosity" are more accurate descriptive terms than "homozygosity" when there are two non-identical expanded HTT alleles. © 2015 Wiley Periodicals, Inc.


Upadhyay J.,St Vincents Hospital | Steenkamp D.,Boston Medical Center | Milunsky J.,Center for Human Genetics Inc.
Endocrine Practice | Year: 2013

Objective: We review the syndrome of hypoparathyroidism, deafness, and renal anomalies (HDR syndrome).Methods: The current understanding and relevant literature pertaining to the background, genetic considerations, clinical features, prognosis, and treatment of HDR syndrome are reviewed.Results: The combination of hypoparathyroidism, deafness, and renal anomalies constitutes an unusual syndrome associated most commonly with haploinsufficiency in GATA3, which encodes a transcription factor that binds to the (A/T) GATA (A/G) consensus DNA sequence. Sensorineural hearing loss is the most consistently expressed clinical feature, being present in almost all affected individuals, and the combination of hypoparathyroidism and hearing impairment occurs in well over 90% of those affected, with various renal anomalies being the most heterogeneous feature of the classic triad. We characterize, in tabular form, the individual cases described in the literature and propose a classification scheme based on the presence or absence of renal anomalies. We also include the specific genetic abnormality and renal anomaly associated with each individual case.Conclusion: HDR syndrome is a heterogeneous syndrome most commonly associated with GATA3 haploinsufficiency. © 2013 AACE.


Shin M.,Boston Medical Center | Douglass L.M.,Boston Medical Center | Milunsky J.M.,Center for Human Genetics Inc. | Paul Rosman N.,Boston Medical Center
Journal of Child Neurology | Year: 2016

Benign paroxysmal torticollis of infancy is an unusual movement disorder, often accompanied by a family history of migraine. Some benign paroxysmal torticollis cases are associated with CACNA1A mutations. The authors sought to determine the frequency of CACNA1A mutations in benign paroxysmal torticollis by testing 8 children and their parents and by searching the literature for benign paroxysmal torticollis cases with accompanying CACNA1A mutations or other disorders linked to the same gene. In our 8 benign paroxysmal torticollis cases, the authors found 3 different polymorphisms, but no pathogenic mutations. By contrast, in the literature, the authors found 4 benign paroxysmal torticollis cases with CACNA1A mutations, 3 with accompanying family histories of 1 or more of familial hemiplegic migraine, episodic ataxia, and paroxysmal tonic upgaze. Thus, CACNA1A mutations are more likely to be found in children with benign paroxysmal torticollis if accompanied by family histories of familial hemiplegic migraine, episodic ataxia, or paroxysmal tonic upgaze. © 2016 The Author(s).


Steenkamp D.W.,Boston Medical Center | Milunsky J.M.,Center for Human Genetics Inc. | Sternthal E.,Boston Medical Center
Endocrine Practice | Year: 2013

Objective: To report a postulated mechanism for resistance to overt ketoacidosis due to prolonged insulin omission in a severely hyperglycemic woman with a 14-year history of autoimmune type 1 diabetes (T1D).Methods: History, physical examination, laboratory testing, and genotyping were performed. We also revie. The medical literature pertinent to this patient's phenotype and genotype.Results: Proinsulin levels remained withi. The normal range (suppressed with hypoglycemia) despite simultaneous almost unmeasurable C-peptide levels during hyperglycemia. We confirmed a homozygous (TT) variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22) 1858T, a T1D susceptibility gene associated with higher proinsulin levels.Conclusion: The extraordinarily preserved proinsulin biological activity may explai. The unusual resistance to overt ketoacidosis despite omission of exogenous insulin administration for extended periods of time. The role o. The associated PTPN22 1858TT variant remains speculative. © 2013 AACE.

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