The microcephaly-capillary malformation syndrome is a highly recognizable severe congenital microcephaly syndrome. Its’ main features are usually identified at or shortly after birth as affected children have a strikingly small head size (or microcephaly), and cutaneous vascular malformations, also known as capillary malformations. These cutaneous lesions are usually scattered all over the body and vary in size from a few millimeters to a few centimeters. Early onset intractable epilepsy occurs in almost all affected children. Other unique features include distal digital hypoplasia (such as short, tapered digits and/or nail hypoplasia), spastic quadriparesis, poor body growth, and profound intellectual disability. Abnormal movements and optic nerve atrophy have been reported in some affected children as well. Brain neuroimaging universally shows microcephaly with simplified gyral pattern and increased extra axial space. Other MRI features include diffuse hypomyelination and variable degrees of hippocampal hypoplasia.

Like most congenital microcephaly syndromes, the microcephaly-capillary malformation syndrome is inherited in an autosomal recessive fashion. Mutations in STAMBP, a gene encoding a deubiquitinating enzyme, were recently identified in 10 affected children, including a pair of siblings from nonconsanguineous parents. The identified mutations include six missense mutations, two non­sense mutations, two translational frameshift mutations predicted to cause a premature truncation of the STAMBP protein and three intronic mutations leading to alternative splicing of the STAMBP transcript. STAMBP encodes the deupiquinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM). This enzyme plays a key role in cell surface receptor–mediated endocytosis and sorting. Reduced STAMBP expression in affected individuals was associated with accumulation of elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. These pathways are well implicated in disorders associated with similar vascular malformations.

Genetic testing for microcephaly-capillary malformation syndrome is available at the University of Chicago Genetic Services.

References:

1. McDonell LM et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat Genet. 2013 Apr 26;45(5):556-62. doi: 10.1038/ng.2602. Epub 2013 Mar 31.
2. Carter MT et al. A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies. Am J Med Genet A. 155A, 301–306 (2011).
3. Mirzaa GM et al. The microcephaly-capillary malformation syndrome. Am J Med Genet A. 155A, 2080–2087 (2011).
4. Isidor B et al. Multiple capillary skin malformations, epilepsy, microcephaly, mental retardation, hypoplasia of the distal phalanges: report of a new case and further delineation of a new syndrome. Am J Med Genet A. 155A, 1458–1460 (2011).

The Department of Human Genetics has American Board of Medical Genetics accredited training programs in clinical molecular genetics and clinical cytogenetics. The training programs have a wide range of clinical and research activities including orphan disease diagnostics, genotype-phenotype correlation studies, cancer genetics, translation of new gene discoveries for diagnostic purposes, technology development, centromere delineation, chromosome structure and function studies, and phenotype/karyotype studies. In addition, other research interests in the department include complex disease genetics, gene mapping, human gene variation and evolution and neurogenetics. 

Dr. Raca completed her molecular genetics fellowship at the University of Chicago in 2004.  She is currently a co-Director of the Cancer Cytogenetics Laboratory at the Department of Medicine at the University of Chicago. 

When and why did you first decide that you wanted to pursue ABMG accredited clinical molecular genetics training at the University of Chicago?

I got interested in the genetic basis of human diseases when I was a medical student in my home country, Serbia. During medical training, I volunteered in a clinical cytogenetics laboratory to learn how chromosomal abnormalities originate, how they lead to abnormal phenotypes and how they can be diagnosed. I enjoyed learning cytogenetic techniques and working in a clinical laboratory, but I realized that chromosomal disorders represented only a small subset of human genetic diseases. My next wish became to get training in molecular genetics, and understand pathogenesis and detection methods for monogenic diseases. Opportunities to get advanced genetic training were limited in Serbia, so I applied to graduate programs in the United States. My plan was to first acquire basic knowledge in molecular genetics, but to ultimately pursue a career in molecular and cytogenetic diagnostics.

The five years of graduate training at the University of Illinois in Chicago were a very happy time.  I finally had an opportunity to study subjects I was very passionate about, and I also enjoyed living in Chicago. The city had so much to offer, even to a graduate student on a very limited budget. I learned to enjoy walks and bike rides by the lake, picnics and beach volleyball tournaments in summer. In winter, my favorite pastime was to sit in the Borders coffee shop by the Water Tower Place, sipping hot chocolate and watching Christmas lights and crowds of people on Michigan avenue.

I made a lot of new friends in graduate school. Several people in my graduate program were also from Serbia, and we became very close, helping each other with problems but also sharing happy moments and doing fun stuff (movie nights, picnics, free concerts…). A possibility to stay in Chicago for my fellowship training in diagnostics seemed very attractive, and I was thrilled to find out that The University of Chicago was in a process of getting accreditation for an ABMG fellowship in Medical genetics, Cytogenetics and Molecular diagnostics. I applied for a postdoctoral position in Soma’s lab and we agreed that I would transition into fellowship training in molecular diagnostics and clinical cytogenetics as soon as the program got approved. That is how I became the first molecular fellow in Soma’s lab in 2002.

Tell me about what you have been doing since you completed the fellowship program at the University of Chicago in 2004?

Before starting my graduate training at the University of Illinois I spent several years working in a clinical cytogenetic laboratory. I love both cytogenetics and molecular diagnostics, and I wanted to get training and Board certification in both these areas.  After completing molecular training in Soma’s lab,  I was accepted to a cytogenetics training program at Emory. I moved to Atlanta in 2004, and stayed there until completing my cytogenetics fellowship in 2006. As I started looking for my first job as an Assistant director, I searched for a laboratory that would allow me to work on all aspects of cytogenetic testing, but to also work in molecular diagnostics. A position at The UW Genetic Laboratory at the University of Wisconsin-Madison and Wisconsin State Laboratory of Hygiene turned out to be a perfect fit. This was a combined cytogenetic and molecular laboratory, offering cytogenetic testing for prenatal, constitutional and cancer cases, array CGH analysis and molecular testing for several constitutional diseases and somatic cancer mutations. I spent five years working in this laboratory, first as an Assistant Director and later as a Co-director.

While my previous training focused mostly on hereditary diseases and constitutional abnormalities, at The UW Genetic Laboratory I worked on a large number of cancer cases and I developed interest in cancer genetics. I also missed Chicago, where I spent almost ten years first as a graduate student and then as a postdoc and molecular fellow. When a position opened for a Co-director of the Cancer Cytogenetic laboratory at the University of Chicago I decided to apply. I moved back to The University of Chicago in summer of 2011. I work now on Cancer cytogenetic testing. It was very nice to come back and find many of my old friends (people I met working in Soma’s lab) still at the University. I am truly impressed and very happy to see how much the Molecular Genetics laboratory has grown in less than 10 years. When I was a fellow, there were only three of us in the clinical part of the laboratory, with two additional people doing research. Nowadays the lab has more than 20 people, two directors, two genetic counselors, a bioinformatics expert, and two, even three fellows at a time. It has grown into one of the most renown molecular diagnostic laboratories in the county, and I feel very proud and privileged that I had an opportunity to train in this laboratory.

How has the fellowship program prepared you for your current position?

Although I currently work in a cytogenetic laboratory, my training in molecular diagnostics is of great benefit. As both fields evolve, there is an increasing overlap between cytogenetic and molecular approaches and techniques. Implementation of whole genome DNA arrays in cytogenetic testing requires that each cytogeneticists understands at least basic molecular methods, and has an ability to optimize and troubleshoot purely molecular procedures like DNA isolation, PCR or hybridization. Fluorescence in situ hybridization analysis is another area with a lot of overlap between cytogenetic and molecular approaches. In addition, to properly understand hematologic malignancies studied by my laboratory, one has to understand how both chromosomal mutations as well as mutations at DNA base level contribute to their development. For cases that we test in the laboratory I frequently have to compare and correlate our cytogenetic results with mutation testing data from molecular pathology.

Since in addition to cytogenetics I also love molecular genetics, I am currently working with the Director of the newly established Division of Genomic and Molecular Pathology on getting more actively involved in routine molecular testing within the division. That way I will hopefully in a near future utilize even more my knowledge and training in molecular diagnostics.  

What do you like most about the city of Chicago?

There are many great thinks about Chicago: the lake with its beaches, parks, and trails, Grand park with its summer concerts, the beautiful architecture and a breathtaking skyline, the Magnificent Mile with its shops and tourists, great museums, theaters and restaurants, Chicago symphony, jazz and blues clubs, sports stadiums, ethnic neighborhoods, friendly and sincere people …..Chicago is a huge city that remains comfortable for living; it is not too hectic, overcrowded and stressful as many other big cities.

Any memorable anecdotes or stories from your time here in the Das lab? 

When I was in the Das lab, we were a small group, and I became very close with the people who worked at the lab: Mark, Carla, Angie, Peixian, Ellen, Stephanie…So I invited all of them to a ‘going away party’ I organized at my place before moving to Atlanta. I also invited my friends from graduate schools and from my home country. At the party I noticed that my co-worker from the lab Mark and a friend from my hometown Sanja spent a lot of time talking to each other and laughing, but I forgot about that as I got busy with my new life in Atlanta. A few months later I got an e-mail from Sanja that the two of them were dating, and that this was developing into a serious relationship.  Mark and Sanja are now married and have a very cute three-year old boy Maxim. I see them often since  I’ve moved back to Chicago, and they are probably my closest friends. This was my first (and so far the only) matchmaking success).

Another very dear friend is Angie, whom I also met working in the Molecular genetics lab. We were both coffee drinkers, and we had a regular afternoon routine to go together to a vending machine in the basement and get our favorite coffee drink. In the meantime Angie graduated from medical school and finished a residency in pathology. She is now a faculty at the Department of Pathology here at the University of Chicago; we still regularly have our coffee, except that we ‘upgraded’ from going to a vending machine to having lattes in the closest Starbucks.  So working in the Das lab, I not only learned a lot about molecular genetics, but I also met wonderful people who became my friends for life.

2013 Angelman Syndrome Foundation

Biennial Conference

“Championing Progress”

July 23-26, 2013

Walt Disney World Swan & Dolphin

Orlando, Florida

The Angelman Syndrome Foundation Biennial Conference provides families of individuals with Angelman syndrome, medical professionals, educators, researchers and AS supporters with an opportunity to come together and discuss the latest developments in managing AS.  Since the first Conference in 1991, the ASF has intensified the quality and quantity of information available to families and professionals, addressing virtually every aspect of AS.  As the largest AS Conference in the world, the ASF is proud to host this valuable event and to underwrite approximately half of the cost associated with hosting the Conference, making it more financially accessible for all families of individuals with AS to attend.

2013 Biennial Conference

Registration for the Angelman Syndrome Foundation’s 2013 Biennial Conference—Championing Progress—is now open!  This year’s Conference will be held July 23-26 at the Walt Disney World Swan & Dolphin resort in Orlando, Florida, and will feature a variety of keynote speakers, breakout sessions, and collaborative opportunities with other attendees. 

The Conference theme, Championing Progress, reflects the remarkable progress made in advancing research, treatments and direct support for individuals with AS and their families during the past few years.  These developments include discovering a potential treatment for AS, opening two Angelman Syndrome Clinics, discovering how a low-glycemic diet can dramatically reduce seizures, further understanding the genetic complexities of AS, and many others. The ASF is honored to continue to collaborate with a variety of institutions and champion the progress being made in improving quality of life for individuals with AS and their families. 

All details related to the Conference are located on the ASF's website, including:

• Registration details
• Conference schedule
• Transportation & travel details
• Hotel accommodations
• Discount attraction tickets
• Exhibitors and sponsors
• Scientific Symposium

As additional information is available pertaining to the Conference, the ASF will update its website and distribute notifications. 

Conference Scholarship

The ASF engages private and corporate donors to raise additional funds to help offset the costs of attending the Conference for families, and uses those funds to offer the ASF Conference Scholarship.  The Scholarship is awarded on a financial need basis and funds are available up to $1,000, which helps cover Conference registration and hotel accommodations.  Families interested must apply by May 9, 2013.  All information provided is kept completely confidential by the ASF.

Visit http://www.angelman.org/ today to register for the Symposium.

The University of Chicago Genetic Services Introduces New Next Generation Sequencing Panels for Rett and Angelman syndrome.

Angelman and Rett syndrome are neurodevelopmental disorders with significant phenotypic overlap. Classic Rett syndrome [OMIM#312750] is a progressive disorder characterized by acquired microcephaly, loss of purposeful hand movements, and autistic behaviors, following a period of normal growth and development. Angelman syndrome [OMIM #105830] is characterized by functionally severe developmental delay or intellectual disability, movement or balance disorders of variable severity, behavioral uniqueness exemplified by apparent happy demeanor (frequent laughing/smiling) and easy excitability, and severe speech impairment .

Our New Rett/Angelman Syndrome Sequencing Panel includes sequencing of the 18 genes listed: ARX, ATRX, CDKL5, CNTNAP2, FOXG1, MECP2, MEF2C, MED17, NRNX1, OPHN1, PCDH19, PNKP, SLC2A1, SLC9A6, TCF4, TRAPPC9, UBE3A, ZEB2

Our New Rett/Angelman Syndrome Deletion/Duplication Panel includes deletion/duplication analysis of the 14 genes listed: ARX, CDKL5, FOXG1, MECP2, MEF2C, MED17, OPHN1, PCDH19, PNKP, SLC2A1, SLC9A6, TCF4, UBE3A, ZEB2.

We are pleased to add this comprehensive panel to our current catalogue of testing for Rett and Angelman syndrome which also includes:

Rett/Atypical Rett Syndrome Panel (MECP2, CDKL5, MEF2C and FOXG1 sequencing and deletion/duplication analysis)

Angelman Syndrome Tier 2 Panel (UBE3A, SLC9A6, MECP2, and TCF4 sequencing and deletion/duplication analysyis)

The University of Chicago Genetic Services Introduces New Next Generation Sequencing Panels for Neonatal Diabetes and Maturity-Onset Diabetes of the Young

Neonatal Diabetes Mellitus (NDM) is diabetes diagnosed within the first 6 months of life and can be characterized as either permanent (PNDM), requiring lifelong treatment, or transient (TNDM), which typically resolves by 18 months of age. NDM is rare with an incidence of approximately 1:1,000,000-260,000 live births.

Maturity-onset diabetes of the young (MODY) is more common than NDM and usually first occurs in children or adolescents but may be mild and not detected until adulthood. It is predicted that MODY accounts for approximately 1-2% of all type 2 Diabetes caes with an incidence of approximately 100 cases per million in the UK population.

Our New Neonatal Diabetes/MODY Syndrome Sequencing Panel* includes sequencing of the 27 genes listed: GCK, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, GATA6, PTF1A, RFX6, ZFP57, GLIS3, EIF2AK3, NEUROG3, INSR, SLC2A2, IER3IP1, WFS1, CISD2, HADH, GLUD1, CP, FOXP3, AKT2

Comprehensive sequence coverage of the coding regions and splice junctions of all genes in this panel will be performed.  Targets of interests will be captured and amplified using Agilent HaloPlex target enrichment system.  The constructed genomic DNA library will be sequenced using Illumina technology and reads will be aligned to the reference sequence.  Variants will be identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors.  All novel and/or potentially pathogenic variants will be confirmed by Sanger sequencing.  The technical sensitivity of this test is estimated to be >99% for single nucleotide changes and insertions and deletions of less than 20bp.

*The most common MODY genes - HNF1A, HNF4A, HNF1B- are not included in this panel due to restrictive licensing conditions imposed for testing of these genes.

The University of Chicago Genetic Services Introduces New Next Generation Sequencing Panels for Lipodystrophies

Lipodystrophies are characterized by generalized or partial absence of adipose tissue and are typically considered in individuals with insulin resistance, significant dyslipidaemia and fatty liver. Lipodystrophies are typically classified according to the anatomical distribution of fat tissue

Our New Congenital Generalized Lipodystrophy Sequencing Panel includes sequencing of the 4 genes listed: AGPAT2, BSCL2, CAV1, PTRF

Our New Partial Lipodystrophy Sequencing Panel includes sequencing of the 7 genes listed: AKT2, CIDEC, LMNA, PLINI, PPARG, TBC1D4, AMPSTE24

Our New Comprehensive Lipodystrophy Sequencing Panel includes sequencing of the 11 genes included in both the Congenital Generalized Lipodystrophy and Partial Lipodystrophy panels

Comprehensive sequence coverage of the coding regions and splice junctions of all genes in this panel will be performed.  Targets of interests will be captured and amplified using Agilent HaloPlex target enrichment system.  The constructed genomic DNA library will be sequenced using Illumina technology and reads will be aligned to the reference sequence.  Variants will be identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors.  All novel and/or potentially pathogenic variants will be confirmed by Sanger sequencing.  The technical sensitivity of this test is estimated to be >99% for single nucleotide changes and insertions and deletions of less than 20bp.

This poster (#0380) will be presented at the ACMG Annual Clinical Genetics Meeting by Daniela del Gaudio, our associate lab director, Thursday March 21: 10:30am-11:30am.  Stop by and learn more

Monogenic diabetes is a group of less common forms of diabetes that account for 1-2% of all diabetes cases.  Monogenic diabetes patients are most often not recognized as being distinct from those with type 1 or type 2 diabetes, even though some forms can frequently be treated very differently.  Thus, if a proper genetic diagnosis is uncovered, it could dramatically improve patient care.  The genetic risk of future offspring or asymptomatic family members could also be established, as well as better prediction of the disease course and possible associated problems.  The most striking example is seen for patients with mutations in the K_ATP channel genes, who can be effectively treated with oral sulfonylurea drugs rather than insulin, resulting in dramatically improved quality of life and control of diabetes.

We developed a panel for selective enrichment of a set of 56 genes known to play a role in monogenic diabetes followed by next generation sequencing (NGS) using the Illumina MiSeq platform.  To amplify the regions of interest we used the HaloPlex PCR target enrichment system (Agilent Technologies).  The total amount of sequence encompassed by the 56 genes is 144 kb and includes the coding region and 20 bp of flanking intronic sequence. In an initial study, five genomic DNA samples with available exome sequencing data were used to evaluate the validity of this system.  The data obtained from the HaloPlex enrichment system and from the exome sequence of the same samples was analyzed using a custom-developed bioinformatic pipeline and 100% concordance in variant calls was observed between the two platforms within the regions of interest of the genes included in the panel. Validation of this platform for clinical use is in progress and will involve the analysis of 50 anonymized samples with known sequence variations previously identified on a research basis by Sanger sequencing.

The availability of this panel will be ben­eficial as 1) it will allow for more rapid and cost-effective diagnosis of patients with monogenic forms of diabetes by analyzing multiple diabetes genes simultaneously and 2) it will provide a significant diagnostic advantage in a substantial fraction of patients where Sanger-based sequencing often is inefficient, such as in cases with atypical clinical presentation or where clinical information is limited.  The overall goal will be an improvement in the diagnosis and treatment of patients with monogenic diabetes. Aside from its valuable diagnostic utility, this panel will also represent an excellent tool for studying a substantial number of patients where previous analyses have failed to identify a genetic defect and will allow for better genotype-phenotype correlation studies.

This poster (#0107) will be presented at the ACMG Annual Clinical Genetics Meeting by Chris Tan, our genetic counselor, Thursday March 21: 10:30am-11:30am.  Stop by and learn more

Primary Autosomal Recessive Microcephaly (MCPH) is a genetically heterogeneous condition characterized by congenital microcephaly, intellectual disability without other neurologic findings, and the absence of facial dysmorphisms or other organ malformations. To date, 8 MCPH loci have been identified and their genetic causes include mutations in the genes encoding MCPH1(MCPH1, OMIM#251200), WDR62 (MCPH2, OMIM#613583), CDK5RAP2 (MCPH3, OMIM#604804), CEP152 (MCPH4, OMIM#613529), ASPM (MCPH5, OMIM#608716), CENPJ (MCPH6, OMIM#608393), STIL (MCPH7, OMIM#612703) and CEP135 (MCPH8, OMIM#614673). The incidence of MCPH appears to be less common in Caucasian populations than in Asian and Arab populations that practice consanguineous marriages.  Prevalence estimates range between 1 in a million in Caucasians up to 1/10,000 in Northern Pakistani populations. We describe the clinical and molecular investigations of a patient with primary microcephaly found to have heterozygous mutations identified in CDK5RAP2, only the fourth and fifth mutations to be described in this gene, the first in an individual that is not from a consanguineous family. 

The patient, a 6 year old female, was the product of a triplet pregnancy born at 33 weeks gestation.  She was noted, in utero, to have a smaller head than either of her sibs.  Upon physical exam at 5 years of age, her height and weight were below the third percentile and head circumference was below the first percentile.  The patient’s facial features were non-dysmorphic, and her chest, heart, lung, abdomen, back, genital and extremity exams were unremarkable.  Primary concern in the patient was her development, including delays in speech, retention, and recognition of numbers and letters.  The family is of Caucasian and Cherokee ancestry on the paternal side and Northern European ancestry on the maternal side. 

A next generation sequencing panel for genes involved in primary microcephaly was performed revealing two novel mutations in CDK5RAP2 (c.524_528delAGGCA and c.4005-1G>A), both of which were predicted to result in deleterious effects.  A review of the published literature to date reveals that only three mutations have been previously reported in the CDK5RAP2 gene in the homozygous state in four Northern Pakistani and Somali consanguineous families.   Our patient represents the first non-consanguineous individual to have been identified with CDK5RAP2- related MCPH.  To date our laboratory has analyzed the CDK5RAP2 gene in 159 patients and data will also be presented on the additional sequence changes identified in this gene.  Our results highlight the utility of multi-gene sequencing panels to elucidate the etiology of genetically heterogeneous conditions.  Our experiences contribute towards the growing amount of data on CDK5RAP2-related MCPH and supports the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations.