Publications by authors named "Jeff Milunsky"

51 Publications

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

Eur J Hum Genet 2020 10 1;28(10):1422-1431. Epub 2020 Jun 1.

Clinical Geneticist Medical Genetics Department, CHUQ-CHUL, Quebec, Canada.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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http://dx.doi.org/10.1038/s41431-020-0654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608102PMC
October 2020

A contiguous microdeletion syndrome at Xp23.13 with non-obstructive azoospermia and congenital cataracts.

J Assist Reprod Genet 2020 Feb 9;37(2):471-475. Epub 2020 Jan 9.

Department of Urology, Boston Medical Center and Boston University School of Medicine, Boston, MA, USA.

Non-obstructive azoospermia accounts for 10-15% of male infertility, resulting in 60% of all cases of azoospermia and affecting about 1% of the male population. About 30% of these cases are due to Y chromosome microdeletions, chromosome abnormalities, or hormonal disorders. Pathogenic variants in genes on the sex chromosomes have key roles in spermatogenic failure. The co-occurrence of azoospermia and congenital cataracts ranges between 1 in 165,000 and 1 in 500,000. Our 28-year-old patient with normal intelligence and abnormally shaped teeth presented with both disorders. A microarray revealed a microdeletion at Xp23.13 with a whole NHS gene deletion as well as a contiguous deletion of two other genes [SCML1 and RAI2]. This observation represents the first report of non-obstructive azoospermia with congenital cataracts and a contiguous deletion of the SCML1 gene, a transcript of which is exclusively expressed in the testis. SCML1 is the putative culprit gene, which requires functional study or animal experiments. Our analysis of 60 known spermatogenesis failure-related genes by whole-exome sequencing revealed no other candidate. The Nance-Horan syndrome due to pathogenic variants in the NHS gene at Xp23.13 including whole gene deletion does not have azoospermia as a feature. Our report adds to the completeness of genetic counseling for an individual with azoospermia and congenital cataracts.
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http://dx.doi.org/10.1007/s10815-019-01685-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056753PMC
February 2020

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Identification of a dominant MYH11 causal variant in chronic intestinal pseudo-obstruction: Results of whole-exome sequencing.

Clin Genet 2019 11 13;96(5):473-477. Epub 2019 Aug 13.

Center for Human Genetics and Dept. Ob/Gyn, Tufts University School of Medicine, Boston, Massachusetts.

Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare gastrointestinal disorder, which affects the smooth muscle contractions of the gastrointestinal tract. Dominant mutations in the smooth muscle actin gene, ACTG2, accounts for 44%-50% of CIPO patients. Other recessive or X-linked genes, including MYLK, LMOD1, RAD21, MYH11, MYL9, and FLNA were reported in single cases. In this study, we used Whole-Exome Sequencing (WES) to study 23 independent CIPO families including one extended family with 13 affected members. A dominantly inherited rare mutation, c.5819delC (p.Pro1940HisfsTer91), in the smooth muscle myosin gene, MYH11, was found in the extended family, shared by 7 affected family members but not by 3 unaffected family members with available DNA, suggesting a high probability of genetic linkage. Gene burden analysis indicates that additional genes, COL4A1, FBLN1 and HK2, may be associated with the disease. This study expanded our understanding of CIPO etiology and provided additional genetic evidence to physicians and genetic counselors for CIPO diagnosis.
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http://dx.doi.org/10.1111/cge.13617DOI Listing
November 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Genet Med 2019 Sep;21(9):2160-2161

University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019

CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions.

Am J Hum Genet 2017 May;100(5):773-788

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address:

Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7) and lysine (K) methyltransferase 2D (KMT2D), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7 or KMT2D identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.
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http://dx.doi.org/10.1016/j.ajhg.2017.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420353PMC
May 2017

Diagnosis of Chronic Intestinal Pseudo-obstruction and Megacystis by Sequencing the ACTG2 Gene.

J Pediatr Gastroenterol Nutr 2017 10;65(4):384-387

*Center for Human Genetics, Cambridge †Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA ‡St. Luke's Regional Medical Center, Boise, ID §University of Washington Center for Mendelian Genomics, Seattle, WA.

Objectives: The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin γ-2 (ACTG2) gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously.

Methods: Whole exome sequencing was performed in 4 probands with chronic intestinal pseudo-obstruction. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands and our 28 (total 111) and determined how many had pathogenic variants and the precise genotype.

Results: Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4 out of 28 of our probands and in 45 out of 83 published probands (49/111 [44.1%]). Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident.

Conclusions: Pooled gene sequencing results from 1 individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50% risk of recurrence, provides an opportunity for genetic counseling.
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http://dx.doi.org/10.1097/MPG.0000000000001608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610062PMC
October 2017

Dental issues in lacrimo-auriculo-dento-digital syndrome: An autosomal dominant condition with clinical and genetic variability.

J Am Dent Assoc 2017 03 30;148(3):157-163. Epub 2016 Dec 30.

Background And Overview: Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant disorder with variable lacrimal and salivary gland hypoplasia and aplasia, auricular anomalies and hearing loss, dental defects and caries, and digital anomalies.

Case Description: The authors present the cases of 2 unrelated children with enamel defects and history of dry mouth leading to recurrent dental caries. The referring diagnoses were Sjögren disease and hypohidrotic ectodermal dysplasia, respectively. The geneticist suspected LADD syndrome, which was confirmed by means of molecular studies showing mutations of 2 genes: fibroblast growth factor receptor 2 and fibroblast growth factor 10, respectively. Similarly affected relatives indicated an autosomal dominant inheritance. These relatives needed multiple dental rehabilitations during childhood and dentures in adulthood.

Conclusions And Practical Implications: Dry mouth, multiple caries, enamel defects, and abnormal tooth morphology were the reasons for seeking care from dentists. However, clinical evaluation and diagnostic imaging studies helped identify anomalies of the lacrimal and salivary glands, ears, and digits, indicating involvement of different areas of the body, compatible with LADD syndrome. Accordingly, dentists should consider genetic disorders in patients with multiple anomalies. For instance, oculodentodigital syndrome, oral-facial-digital syndrome, and LADD syndrome (among others) may have dental issues as the major clinical manifestation. Accurate identification of a particular syndrome is now commonplace with the use of genetic testing. When a patient has multiple anomalies suggestive of a syndromic condition, appropriate genetic testing can help verify the clinical diagnosis. Keeping genetics in mind helps earlier identification of other affected family members with diagnostic genetic testing and appropriate treatment; the economic advantage is to shorten the diagnostic odyssey and possibly preserve dentition.
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http://dx.doi.org/10.1016/j.adaj.2016.11.016DOI Listing
March 2017

The Genetics of Benign Paroxysmal Torticollis of Infancy: Is There an Association With Mutations in the CACNA1A Gene?

J Child Neurol 2016 07 9;31(8):1057-61. Epub 2016 Mar 9.

Departments of Pediatrics and Neurology, Division of Pediatric Neurology, Boston Medical Center, Boston, MA, USA

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.
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http://dx.doi.org/10.1177/0883073816636226DOI Listing
July 2016

Familial transmission of 5p13.2 duplication due to maternal der(X)ins(X;5).

Eur J Med Genet 2015 May 6;58(5):305-9. Epub 2015 Apr 6.

Center for Human Genetics, Inc., Cambridge, MA, USA. Electronic address:

Submicroscopic duplications of 5p13 have been recently reported in several cases, warranting the description of a new clinical entity (Chromosome 5p13 Duplication Syndrome; MIM 613174). These microduplications, while variable in size, all contain at least part of the NIPBL gene. Patients with duplications in this region present with intellectual disability/developmental delay (ID/DD) and dysmorphic facies. In addition, skeletal and brain abnormalities have been variably reported, as well as propensity for obesity in adulthood and hypotonia. We report a family with two affected sons and two affected daughters, each carrying a duplication at 5p13.2 encompassing the 3' portion of SLC1A3 and the 5' portion of NIPBL. Upon confirming the SNP microarray finding by FISH in the proband, it was discovered that the 5p13.2 duplication was located on the short arm of the X chromosome. Further FISH studies on the family demonstrated that all affected children and their mother carried a derivative X chromosome with insertion of material from 5p13.2 into the intermediate region of Xp [der(X)ins(X;5)(p2?2.1;p13.2p13.2)]. To our knowledge, this is the first report of an inherited duplication of 5p13.2 with multiple affected family members. This family underscores the need to confirm array findings by FISH, both in the proband and family members, to discern implications for pathogenicity and more accurately define the recurrence risk.
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http://dx.doi.org/10.1016/j.ejmg.2015.03.004DOI Listing
May 2015

Biallelic mutations in huntington disease: A new case with just one affected parent, review of the literature and terminology.

Am J Med Genet A 2015 May 3;167A(5):1152-60. Epub 2015 Mar 3.

Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.

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.
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http://dx.doi.org/10.1002/ajmg.a.37009DOI Listing
May 2015

Identification of Critical Region Responsible for Split Hand/Foot Malformation Type 3 (SHFM3) Phenotype through Systematic Review of Literature and Mapping of Breakpoints Using Microarray Data.

Microarrays (Basel) 2015 Dec 24;5(1). Epub 2015 Dec 24.

Center for Human Genetics, Cambridge, MA 02139, USA.

Split hand/foot malformation (SHFM) is a limb malformation with underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. There are six types of SHFM. Here, we report a boy with SHFM type 3 having normal 4th and 5th digits, absent 2nd and 3rd digits, and a 4th finger flexion deformity, as well as absent 2nd, 3rd and 4th toes bilaterally. His father, two paternal uncles, and two paternal first cousins have similar phenotype. Chromosome analysis showed a normal male karyotype. A 514 kb gain at 10q24.31-q24.32 (chr10:102,962,134-103,476,346, hg19) was identified using 6.0 Single nucleotide polymorphism (SNP) microarray, resulting in the duplication of nine genes, including BTRC and FBXW4. A detailed systematic review of literature and mapping of breakpoints using microarray data from all reported cases in PubMed and DECIPHER were conducted, and exon 1 of BTRC gene was identified as the critical region responsible for the SHFM3 phenotype. The potential mechanism and future studies of this critical region causing the SHFM3 phenotype are discussed.
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http://dx.doi.org/10.3390/microarrays5010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003447PMC
December 2015

The syndrome of hypoparathyroidism, deafness, and renal anomalies.

Endocr Pract 2013 Nov-Dec;19(6):1035-42

Department of Internal Medicine, St Vincent's Hospital, Worcester, Massachusetts.

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.
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http://dx.doi.org/10.4158/EP13050.RADOI Listing
July 2014

Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.

N Engl J Med 2013 May 8;368(21):1992-2003. Epub 2013 May 8.

Department of Neurology, Massachusetts General Hospital, Boston 02115, USA.

Background: The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.

Methods: We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.

Results: Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis.

Conclusions: The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1215993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738065PMC
May 2013

Preserved proinsulin production in homozygous protein tyrosine phosphatase nonreceptor type 22 C1858T variant type 1 diabetes: a possible explanation for absence of overt ketoacidosis despite omission of exogenous insulin.

Endocr Pract 2013 May-Jun;19(3):426-30

Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118 , USA.

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 review the medical literature pertinent to this patient's phenotype and genotype.

Results: Proinsulin levels remained within 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 explain the unusual resistance to overt ketoacidosis despite omission of exogenous insulin administration for extended periods of time. The role of the associated PTPN22 1858TT variant remains speculative.
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http://dx.doi.org/10.4158/EP12286.ORDOI Listing
February 2014

Updates in the genetic evaluation of the child with global developmental delay or intellectual disability.

Semin Pediatr Neurol 2012 Dec;19(4):173-80

Center for Human Genetics, Inc., Cambridge, MA 02139, USA.

Global developmental delay (GDD) and intellectual disability (ID) occur in up to 3% of the general population and are even more commonly encountered in the setting of the pediatric neurology clinic. New advances in technology and in the understanding of genetic disorders have led to changes in the diagnostic approach to a child with unexplained GDD or ID. Chromosomal microarray has become a first-line test for evaluation of patients in this population and has both significantly increased diagnostic yield and introduced new challenges in the interpretation of copy number variants of uncertain significance. The G-banded karyotype is now frequently utilized as an adjunct to the microarray rather than as a first-line test in individuals with GDD or ID. Fragile X DNA testing continues to be recommended in the initial evaluation of the child with GDD or ID. The presence or absence of certain cardinal features (such as microcephaly or macrocephaly, seizures, autism, abnormal neurologic examination, and facial dysmorphism) can be utilized to direct single-gene molecular testing. The availability of next-generation and massively parallel sequencing technologies has enabled the use of genetic testing panels, in which dozens of genes associated with GDD or ID may be rapidly analyzed. Most recently, the clinical availability of whole-genome and whole-exome sequencing has opened new possibilities for the evaluation of individuals with GDD or ID who have previously eluded a genetic diagnosis. Consultation with a medical geneticist is recommended when progressing beyond first-tier analyses to most efficiently prioritize testing.
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http://dx.doi.org/10.1016/j.spen.2012.09.004DOI Listing
December 2012

Middle and inner ear malformations in mutation-proven branchio-oculo-facial (BOF) syndrome: case series and review of the literature.

Am J Med Genet A 2012 Aug 18;158A(8):1977-81. Epub 2012 Jun 18.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Hearing impairment is common in individuals with branchio-oculo-facial (BOF) syndrome. The majority of described individuals have conductive hearing impairment due to malformed ossicles and/or external canal stenosis or atresia, although a sensorineural component to the hearing impairment in BOF syndrome is increasingly being reported. Sophisticated computed tomography (CT) of the temporal bone has revealed middle and inner ear malformations in three previous reports. We present middle and inner ear abnormalities in three additional individuals with mutation-proven BOF syndrome. We suggest that temporal bone CT imaging be included in the medical workup of a child with BOF syndrome, in order to guide management.
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http://dx.doi.org/10.1002/ajmg.a.35436DOI Listing
August 2012

RASA1 analysis guides management in a family with capillary malformation-arteriovenous malformation.

J Pediatr Genet 2012 Jun;1(2):125-9

Center for Human Genetics, Boston University School of Medicine, Boston, MA, USA; Departments of Pediatrics/Genetics and Genomics, Boston University School of Medicine, Boston, MA, USA.

Capillary malformation-arteriovenous malformation (CM-AVM; MIM 60354) is an autosomal dominant disorder characterized by multifocal cutaneous capillary malformations, often in association with fast-flow vascular lesions, which may be cutaneous, subcutaneous, intramuscular, intraosseus, or cerebral arteriovenous malformations or arteriovenous fistulas. CM-AVM results from heterozygous mutations in the RASA1 gene. Capillary malformations of the skin are common, and clinical examination alone may not be able to definitively diagnose-or exclude- CM-AVM. We report a family in which the proband was initially referred for a genetic evaluation in the neonatal period because of the presence of a cardiac murmur and minor dysmorphic features. Both he and his mother were noted to have multiple capillary malformations on the face, head, and extremities. Echocardiography revealed dilated head and neck vessels and magnetic resonance imaging and angiography of the brain revealed a large infratentorial arteriovenous fistula, for which he has had two embolization procedures. RASA1 sequence analysis revealed a heterozygous mutation, confirming his diagnosis of CM-AVM. We established targeted mutation analysis for the proband's mother and sister, the latter of whom is a healthy 3-year-old whose only cutaneous finding is a facial capillary malformation. This revealed that the proband's mother is also heterozygous for the RASA1 mutation, but his sister is negative. Consequently, his mother will undergo magnetic resonance imaging and angiography screening for intracranial and spinal fast-flow lesions, while his sister will require no imaging or serial evaluations. Targeted mutation analysis has been offered to additional maternal family members. This case illustrates the benefit of molecular testing in diagnosis and making screening recommendations for families with CM-AVM.
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http://dx.doi.org/10.3233/PGE-2012-020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021014PMC
June 2012

A family with branchio-oculo-facial syndrome with primarily ocular involvement associated with mutation of the TFAP2A gene.

Ophthalmic Genet 2012 Jun 22;33(2):100-6. Epub 2011 Dec 22.

Pediatric Ophthalmology, Department of Ophthalmology and Visual Science, University of Iowa Hospital and Clinics, Iowa City, IA 52246, USA.

Background: Branchio-Oculo-Facial syndrome (BOFS) is a rare, autosomal dominant developmental disorder that has a distinct phenotype with characteristic craniofacial abnormalities. We report a family with extensive ocular manifestations of BOFS caused by a novel mutation in the transcription factor AP-2 alpha (TFAP2A) gene.

Materials And Methods: Case report of phenotypic and genotypic characterization of a family with BOFS.

Results: An infant presenting with anophththalmia/coloboma and subtle craniofacial symptoms was found to have a family history of congenital cataracts and colobomas in her mother. A mutation in the TFAP2A gene associated with BOFS (heterozygous H384Y in exon 7) was found in both the proband and her mother. This mutation had not been reported previously. Compared with other molecularly confirmed cases in the literature, this family has primarily ocular features, which are severe.

Conclusions: BOFS can have profound ocular involvement without prominent extraocular features. When the syndrome presents in this way, it may be confused with isolated autosomal dominant chorioretinal coloboma. Testing for mutations in the TFAP2A gene is recommended to establish an accurate diagnosis for the family.
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http://dx.doi.org/10.3109/13816810.2011.634878DOI Listing
June 2012

Partial trisomy 8 mosaicism due to a pseudoisodicentric chromosome 8.

Am J Med Genet A 2011 Jul 10;155A(7):1740-4. Epub 2011 Jun 10.

Center for Human Genetics, Boston University School of Medicine, Massachusetts, USA.

Chromosome 8 is the largest autosome in which mosaic trisomy is compatible with life. Constitutional trisomy 8 (T8) is estimated to occur in approximately 0.1% of all recognized pregnancies. The estimated frequency of trisomy 8 mosaicism (T8M), also known as Warkany syndrome, is about 1/25,000 to 50,000 liveborns, and is found to be more prevalent in males than females, 5:1. T8M is known to demonstrate extreme clinical variability affecting multiple systems including central nervous, ocular, cardiac, gastrointestinal, genitourinary, and musculoskeletal. There appears to be little correlation between the level of mosaicism and the extent of the clinical phenotype. Additionally, the exact mechanism that causes the severity of phenotype in patients with T8M remains unknown. We report on a mildly dysmorphic male patient with partial low-level T8M due to a pseudoisodicentric chromosome 8 with normal 6.0 SNP microarray and high resolution chromosome analyses in lymphocytes. The aneuploidy was detected in fibroblasts and confirmed by FISH in lymphocytes. This report elaborates further the clinical variability seen in trisomy 8 mosaicism.
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http://dx.doi.org/10.1002/ajmg.a.34073DOI Listing
July 2011

De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.

Biol Psychiatry 2011 May 15;69(9):898-901. Epub 2011 Jan 15.

Centre of Excellence in Neuromics of Université de Montréal and Synapse to Disease, S2D, Group, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, Canada.

Background: Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID.

Methods: To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals.

Results: We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects.

Conclusions: We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.
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http://dx.doi.org/10.1016/j.biopsych.2010.11.015DOI Listing
May 2011

Genotype-phenotype analysis of the branchio-oculo-facial syndrome.

Am J Med Genet A 2011 Jan;155A(1):22-32

Center for Human Genetics, Boston University School of Medicine, Massachusetts 02118, USA.

Branchio-oculo-facial syndrome (BOFS; OMIM#113620) is a rare autosomal dominant craniofacial disorder with variable expression. Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. Having determined that mutations involving TFAP2A result in BOFS, we studied a total of 30 families (41 affected individuals); 26/30 (87%) fulfilled our cardinal diagnostic criteria. The original family with the 3.2 Mb deletion including the TFAP2A gene remains the only BOFS family without the typical CL/P and the only family with a deletion. We have identified a hotspot region in the highly conserved exons 4 and 5 of TFAP2A that harbors missense mutations in 27/30 (90%) families. Several of these mutations are recurrent. Mosaicism was detected in one family. To date, genetic heterogeneity has not been observed. Although the cardinal criteria for BOFS have been based on the presence of each of the core defects, an affected family member or thymic remnant, we documented TFAP2A mutations in three (10%) probands in our series without a classic cervical cutaneous defect or ectopic thymus. Temporal bone anomalies were identified in 3/5 patients investigated. The occurrence of CL/P, premature graying, coloboma, heterochromia irides, and ectopic thymus, are evidence for BOFS as a neurocristopathy. Intrafamilial clinical variability can be marked. Although there does not appear to be mutation-specific genotype-phenotype correlations at this time, more patients need to be studied. Clinical testing for TFAP2A mutations is now available and will assist geneticists in confirming the typical cases or excluding the diagnosis in atypical cases.
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http://dx.doi.org/10.1002/ajmg.a.33783DOI Listing
January 2011

Mosaic Down syndrome in a patient with low-level mosaicism detected by microarray.

Am J Med Genet A 2010 Dec;152A(12):3154-6

Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Down syndrome (DS) is the most common aneuploidy in liveborns with an estimated frequency of 1 in 650-1,000 births. Approximately 1-2% of all live-born DS individuals have mosaicism. The correlation between the percentage of mosaicism and the severity of the phenotype in mosaic trisomy 21 has been determined in previous studies. Patients with low percent of trisomy 21 have less phenotypic manifestations, higher IQs, and better overall survival. We report on a 1-day-old baby girl with subtle features of DS and low-level trisomy 21 mosaicism (8-13% in lymphocytes, 31% in buccal cells) with normal high resolution chromosome analysis. The aneuploidy was detected by 6.0 SNP microarray and confirmed by fluorescent in situ hybridization (FISH). Further studies to detect mosaicism are recommended from blood (using interphase FISH) or other tissues in the evaluation of a child with features of DS and a normal blood metaphase karyotype. SNP microarray technology appears to be a useful adjunct, being able to detect low-level mosaicism in these cases.
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http://dx.doi.org/10.1002/ajmg.a.33739DOI Listing
December 2010

Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome.

Am J Med Genet A 2010 Oct;152A(10):2475-81

Center for Human Genetics, Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Epilepsy and Mental Retardation Limited to Females (EFMR) [OMIM 300088] was first described in 1971 [Juberg and Hellman, 1971] in 15 related females with early onset grand mal seizures and mental retardation. Although EFMR demonstrates X-linked inheritance, it follows an unusual pattern by sparing transmitting males and affecting only heterozygous females. In 2008, mutations within the protocadherin 19 (PCDH19) gene were implicated as causative of EFMR [Dibbens et al. (2008); Nat Genet 40:776-781]. The EFMR phenotype is typically characterized by seizure onset in infancy and mild to severe intellectual impairment. Several individuals with EFMR have also been described as having autistic features. We describe three unrelated female individuals, ranging in age from 3 to 19 years, with de novo novel PCDH19 mutations. All three individuals have seizure onset in infancy and require the use of multiple antiepileptic drugs. They also have varying degrees of intellectual impairment along with the presence of autistic features. Although most individuals with EFMR described to date demonstrate this unusual familial X-linked inheritance, our three unrelated females with de novo mutations highlight the importance of testing PCDH19 in females with early onset epilepsy, intellectual impairment, and autistic features, regardless of family history.
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http://dx.doi.org/10.1002/ajmg.a.33611DOI Listing
October 2010

A palindrome-mediated recurrent translocation with 3:1 meiotic nondisjunction: the t(8;22)(q24.13;q11.21).

Am J Hum Genet 2010 Aug 30;87(2):209-18. Epub 2010 Jul 30.

The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Palindrome-mediated genomic instability has been associated with chromosomal translocations, including the recurrent t(11;22)(q23;q11). We report a syndrome characterized by extremity anomalies, mild dysmorphia, and intellectual impairment caused by 3:1 meiotic segregation of a previously unrecognized recurrent palindrome-mediated rearrangement, the t(8;22)(q24.13;q11.21). There are at least ten prior reports of this translocation, and nearly identical PATRR8 and PATRR22 breakpoints were validated in several of these published cases. PCR analysis of sperm DNA from healthy males indicates that the t(8;22) arises de novo during gametogenesis in some, but not all, individuals. Furthermore, demonstration that de novo PATRR8-to-PATRR11 translocations occur in sperm suggests that palindrome-mediated translocation is a universal mechanism producing chromosomal rearrangements.
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http://dx.doi.org/10.1016/j.ajhg.2010.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917714PMC
August 2010

A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a patient with autism.

Am J Med Genet A 2010 Aug;152A(8):2112-4

Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1002/ajmg.a.33497DOI Listing
August 2010