We are pleased to announce the newest addition to our staff, Amy Knight Johnson.  She received her Bachelor of Science degree in genetics from the University of Nottingham, England, and her Master of Science degree in genetic counseling from Northwestern University. Prior to joining the University of Chicago Genetic Services, Amy worked as a Genetic Counselor at the Fetal and Neonatal Medicine Center at Rush University, where she provided care for families with fetal anomalies and other prenatal indications as part of a multidisciplinary team. In addition, she also provided genetic counseling services in the general pediatric and adult genetics clinics at Rush, and supervised genetic counseling students as an Adjunct Faculty member for the Northwestern University Genetic Counseling Program. Amy is excited to be joining the Genetic Services team, and is looking forward to being involved in the launch of our Next-Generation sequencing panels in the future!

The Angelman Syndrome Foundation is pleased to invite you to our Scientific Symposium at the Hilton Washington DC/Rockville, in Rockville, MD on June 25 & 26. The information presented at this educational event should improve your ability to research, treat and manage Angelman syndrome, exchange and share projects and experiences with other members of national Angelman Syndrome Associations, and collaborate on research for Angelman syndrome, UBE3A and those affected by mutations of this gene.

The topic for June 25th will be on the Neuroscience of UBE3A from Genes to Behavior. Distinguished researchers presenting include: Dr. Seth Margolis, Johns Hopkins University, Baltimore, MD; Dr. Mark Zylka, University of North Carolina, Chapel Hill, NC; Dr. Chris Cowan, University of Texas Southwestern Medical Center, Dallas, TX; Dr. Matt Anderson, Harvard Medical School, Boston, MA; Dr. Stormy Chamberlain, University of Connecticut Health Center, Farmington, CT; Dr. Janine LaSalle, UC Davis School of Medicine, Davis, CA; Dr. Yves Pommier, National Cancer Institute, Bethesda, MD; and Dr. Peter Howley, Harvard Medical School, Boston, MA.

In addition to Monday's discussions on the Neuroscience of UBE3A from Genes to Behavior, Tuesday’s sessions will include short presentations with opportunities for questions to follow. Please consider submitting an abstract for consideration in the following areas as it relates to AS: Diagnosis, Communication, Genetics, Neuromotor development, Orthopedics, Behavioral management, Neurosciences, Pharmacology, Epilepsy, Ophthalmology, Cellular biology, Metabolism, Gastroenterology, and Sleep Disturbances.

Researchers will have a unique opportunity to present the very latest findings of their work and compare notes with colleagues from around the globe. Professionals from all parts of the world will have a great opportunity to learn the latest scientific facts about this rare disorder from the foremost authorities. The symposium, in short, will be an event that allows us to share what we know locally, nationally and internationally.

Hotel reservations must be made by June 1 by calling 1-800-HILTONS. Please mention that you are with the Angelman Syndrome Foundation to receive the group rate of $99.00 single/double per night plus tax.

Hilton Washington DC/Rockville Hotel

1750 Rockville Pike

Rockville, MD 20852

Tel (301) 468-1100 / Fax (301) 468-0308

www.washingtondcrockville.hilton.com

Visit http://secure.angelman.org/event/symposium today to register for the Symposium. For more information, please contact Sheila Wenger via telephone at 800-432-6435, or via email at swenger@angelman.org.

The genetic basis for Weaver syndrome recently has been identified (Tatton-Brown et al., Oncotarget, 2011, 2:1127-1133 and Gibson et al., Am. J. Hum. Genet. 2012, 90:110-118) allowing now for the possibility of genetic testing for this disorder.  Weaver syndrome is a rare congenital developmental disorder that was first identified and described in two unrelated males in 1974 by Dr. David Weaver and associates.  Clinical features include generalized overgrowth, advanced bone age, marked macrocephaly, and characteristic facial features.  Among the facial features seen are a broad forehead, ocular hypertelorism, long philtrum, retrognathia with a prominent chin crease that has sometimes been described as a ‘stuck-on’ chin, and large ears.  Several of the patients also have intellectual disability generally in the mild to moderate range.  Weaver syndrome is generally a sporadic condition although some familial cases have been described.

Many of the clinical features of Weaver syndrome overlap with Sotos syndrome, another overgrowth condition, and include in particular macrocephaly, overgrowth, and developmental delay.  Mutations and deletions of the NSD1 gene, which codes for a histone methyl transferase, have been identified in the majority of patients with Sotos syndrome, and a few patients thought to have Weaver syndrome also have had NSD1 mutations.  These latter findings have raised the question of whether Weaver and Sotos syndromes represent allelic disorders with variable expressivity or if they are distinct conditions with different underlying genetic bases. 

A defective gene in Weaver syndrome has recently been identified.  Two groups (Tatton-Brown et al., Oncotarget, 2011, 2:1127-1133 and Gibson et al., Am. J. Hum. Genet. 2012, 90:110-118) used exome sequencing of selected patients with Weaver syndrome and their parents to look for de novo mutations.  One of the patients used in these studies included the original patient described by Dr. Weaver et al. in 1974.  Both studies identified mutations in the EZH2 gene, a gene that codes for a histone modification enzyme.  Specifically, the EZH2 protein catalyzes the trimethylation of lysine 27 of histone H3 (H3K27), thereby playing a key role in the shutting down of transcription of genes that are bound by this histone complex.  The majority of EZH2 mutations identified in patients with Weaver syndrome so far include missense mutations, some in-frame mutations, and very few nonsense/frameshift mutations.  Altogether, EZH2 mutations in 22 unrelated patients with Weaver syndrome have been identified of which one was identified in a familial case.  It is uncertain as to whether the mutations lead to gain or loss of function, but the speculation is that the mutations are more likely to be gain of function mutations.

It is interesting to note that somatic mutations of EZH2 previously have been identified in patients with lymphoid and myeloid malignancies.  In fact some of the same mutations identified in patients with Weaver syndrome have been seen somatically in patients with myeloid malignancies.  Some patients with Weaver syndrome have developed tumors and malignancies leading to the speculation that constitutive EZH2 mutations may confer a predisposition to malignancy.  These observations are still preliminary and more long-term clinical studies of patients with Weaver syndrome will be required to make more definite conclusions about the gene and malignancies in this condition.

EZH2 is the second histone methyl transferase, after NSD1, connected to overgrowth disorders and both are SET-domain containing proteins.  Somatic mutations affecting both the EZH2 and NSD1 genes have been identified in hematologic malignant conditions.  This observation raises the importance of the role of histone-modifying proteins in neurodevelopmental disorders and hematologic malignancies.  With the similarity in phenotype between Weaver and Sotos syndrome, it is satisfying to observe a similar molecular basis for both disorders.

Mutation analysis of the EZH2 and NSD1 genes is available at the University of Chicago Genetic Services Laboratory.  As more patients with mutations in EZH2 are identified through genetic testing, it will be interesting to see if the clinical spectrum of this condition expands.

The University of Chicago Genetic Services Laboratory is an active supporter of the CdLS foundation activities and is pleased to provide some information on the upcoming CdLS scientific symposium.

The nationally recognized Cornelia de Lange Syndrome (CdLS) Scientific Symposium brings together experts in CdLS to share the latest scientific and clinical research and treatments related to the syndrome.

The Symposium is June 20 and 21, 2012, at the Lincolnshire Marriott Resort, Lincolnshire, IL. It precedes the CdLS Foundation’s national biennial family conference.

Professionals from the fields of pediatrics, gastroenterology, genetics, dentistry, behavior, and basic science gather for the one-and-a-half day meeting, supported by the National Institutes of Health.

Symposium objectives include:

• To update knowledge of the broad spectrum of findings in the natural history of CdLS.
• To understand and gain knowledge of the molecular basis for CdLS.
• To obtain knowledge of animal model studies related to CdLS and applications for these findings.

Continuing Medical Education and Continuing Education Units for some specialties are provided. In addition, credits are available through the Illinois Early Intervention program.

The CdLS Foundation is a national not-for-profit 501(c) (3), incorporated in 1981 and based in Avon, CT. The Foundation is a family-support organization that works to promote early and accurate diagnosis of CdLS, while raising overall awareness of the syndrome, promoting research into the causes and manifestations of the condition, and assisting those with CdLS throughout their lives.  Presently, the group provides support and service to approximately 2,500 families, 10,000 relatives and 2,500 professionals across the nation.  

For information and to register, call the CdLS Foundation at 800-753-2357 or email familysupport@CdLSusa.org.

Anne Mitchell sensed something was not quite right when the fetus in her first pregnancy did not move as she had been told to expect.  When her son Michael was born, he was extremely hypotonic and weak, requiring immediate intubation and a trip to the NICU.  Without any family history of similar issues, Anne and David Mitchell did not have any idea why Michael’s muscles were so weak.  After various tests all came back negative, Michael had a muscle biopsy at 4 weeks of age and was diagnosed with centronuclear myopathy.  

Centronuclear myopathy (CNM) is an umbrella term for a group of related hereditary congenital myopathies characterized by variable muscle weakness and hypotonia with onset from birth through adulthood.  Intelligence and cardiac muscles are generally not affected.  Mutations in the MTM1, DNM2, RYR1, and BIN1 genes have been associated with different forms of CNM, including X-linked, dominant, and recessive inheritance patterns.  MTM1 mutations are associated with a specific form of CNM called X-linked myotubular myopathy (XLMTM), which generally causes infantile onset of severe muscle weakness that often leads to feeding and respiratory issues. 

Given Michael’s early onset of weakness, MTM1 testing was ordered through the University of Chicago Genetic Services Laboratory, and the results confirmed that Michael had an MTM1 mutation and XLMTM.  Although it was hard for Anne and David to hear the results, they also found it helpful and reassuring to know the definite diagnosis.  The diagnosis gave the Mitchell family a sense of identity to embrace and empowered them to seek out medical specialists and experts, including the Beggs Congenital Myopathy Research Program at Children’s Hospital in Boston.   Most importantly, Michael and his family were able to connect with other families and become a part of the broader XLMTM community. 

Carrier testing confirmed that Anne was a carrier of the MTM1 mutation, as seen in more than 80% of XLMTM mothers.  Although it was not a determining factor in their family planning, Anne and David found the information helpful, particularly for sharing with family members.  Anne’s mother was not a carrier, suggesting that the mutation was de novo.  Given the risk of germline mosaicism, Anne’s sister also pursued testing and was found not to be a carrier.

After spending the first three months of his life in the neonatal ICU, Michael was transferred to a rehabilitation center for a brief stay and then transitioned home at four months of age to live with his parents.  Michael is now 10 years old and is in the 4th grade.  He uses a wheelchair and requires 24-hour respiratory support, but he and his parents do not let this limit him.  He loves sports, animals, going to school, and spending time with his family.  

Names and other identifying information have been changed in order to protect this family’s privacy.

The University of Chicago provides testing of the TCF4 gene for Pitt Hopkins syndrome. www.pitthopkins.org is an organization established by two families to help others with this diagnosis.  Below is an article by one of the founders, Sue Routledge, that introduces you to her experience with the creation of their support group organization:

When parents realize that their baby is not developing as they expected they want to know how to help them but they also want to know why their child is different. When a child has, in fact, a very rare condition it makes it very hard to find this out, especially when there is no blood test available. This was the case with Pitt Hopkins Syndrome (PTHS) until July 2007 when researchers discovered the responsible gene and developed diagnostic tests. Since then if a child is found to have a mutated or deleted TCF4 gene on chromosome 18q they are diagnosed with Pitt Hopkins Syndrome.

In October 2007, our family in Europe, got a phone call from our geneticist telling us our son of nearly 16 years old had a diagnosis. As he was part of a research project we did not even know he was being tested. Completely out of the blue we discovered he had Pitt Hopkins Syndrome and we did not know anything about it - even the name was a mouthful! We were told there were probably less than 60 confirmed cases worldwide. We managed to access a few research papers but everything was in pure scientific language and sounded very negative. We wanted to talk to other parents but could not find anyone else with the diagnosis. We searched through rare syndrome groups but no one had any information and it was suggested we start a support group! That’s a good idea if you know someone else with a child with Pitt Hopkins. It was so frustrating to have a diagnosis after so many years but not to know anyone else!  “Contact a Family,” a UK-based charity, suggested we put a message on the Making Contact and NORD (National Organization for Rare Disorders) sites in the US.

Two days after we posted a message on NORD we heard from a family in the States whose 16-month-old daughter was diagnosed just 5 days earlier.  We wrote back and forth and discussed starting an online support group at such time as we found another family. We heard from no one else until the following March when two mothers from the States contacted us on NORD.

All the families were interested in the idea of setting up an Internet support group. On April 13^, 2008, the Pitt Hopkins Syndrome Google Group Support group was created by Theresa and Paul, from North Carolina (parents of Victor), and us, Sue and Brian from the Netherlands (parents of Christopher).  That first week there were 4 members. A year later we had about 30 members. Now almost 4 years later we have over 160 members, with a new family joining every couple of weeks on average.  As of March 2012 we have families from the US, Canada, the Netherlands, the UK, Ireland, Germany, France, Italy, Spain, Portugal, Switzerland, Austria, Denmark, Belgium, Sweden, Norway, Crete, Brazil, Australia, and New Zealand. 

Theresa and Sue are the Pitt Hopkins Syndrome Support Group managers. This group is a place to find support and parent information about PTHS. It  has been created to bring together the ideas, thoughts, and hopes of people caring for loved ones with Pitt Hopkins Syndrome.

 To join this support group please follow the link: http://groups.google.com/group/pitt-hopkins/about.  We also have a website at www.pitthopkins.org

Come visit us in the exhibitor hall at the 2012 American College of Medical Genetics Annual Clinical Meeting in Charlotte, NC

March 28-30, Charlotte Convention Center, Booth 413

Copy number variations (CNVs) have been well documented to contribute significantly to some genetic disorders; however their frequency is currently not well established in many rare conditions. Here we describe the development, validation and clinical implementation of a custom oligonucleotide-based array CGH platform for the detection of exonic deletions and duplications in 54 genes, primarily implicated in neurodevelopmental disorders, for which our laboratory currently offers clinical sequence analysis. For the majority of the genes included in this design, the frequency of pathogenic copy number variation is currently unknown.  Selected genes include brain malformation genes, genes implicated in infantile epileptic encephalopathy, Rett/Atypical Rett syndrome, Angelman syndrome, as well as several other genes associated with orphan Mendelian genetic diseases. This custom array, designed by Agilent technologies and printed in an 8x60K format, contains approximately 50,000 probes more densely distributed across the exons of the genes being tested.  The array has been designed to detect exonic copy number changes as small as 300-400 bp.  The performance of this array and its potential application as a diagnostic tool has been evaluated by testing 48 blinded control samples, 33 of which contained a previously characterized abnormality ranging from multiple exons to single exonic CNVs.  The results of this validation study demonstrated that the array-CGH platform unambiguously detected all the expected aberrations and no copy number changes were identified in the remainder 15 negative samples. As of August 2011 we analyzed 111 clinical samples referred to our clinical laboratory for deletion/duplication testing, however disease-associated copy number variations have not been identified. In one patient with global developmental delay, regression and seizures, we identified a previously unreported gain of exons 13 and 14 in the microcephalin gene (MCPH1) that was also present in his phenotypically normal father.  Duplications of the 8p23.1 region that include the MCPH1 gene have previously been described in some families with an autism spectrum disorder.  These preliminary results obtained from a small cohort of patients with heterogeneous clinical presentation corroborate the presumption that the frequency of CNVs in these conditions is rare, that sequence analysis would still be considered the first tier of testing and that genetic diagnosis is also dependent on accurate clinical assessment of these patients’ phenotypes.

This poster (#460) will be presented at the ACMG Annual Meeting by Yu-Wei Cheng, our molecular fellow, Friday March 30: 10:30-11:30 am. Stop by and learn more.

Autosomal recessive primary microcephaly (MCPH) is characterized by congenital microcephaly and mental retardation (MR) with no other neurological findings.  Mutations in the ASPM gene are the most common etiology of MCPH, causing approximately 40% of cases with a strict diagnosis of MCPH.  Several other genes, including CDK5RAP2, CENPJ, MCPH1, STIL, and CEP152 have been reported to cause MCPH in a small number of families.  These genes are all thought to play a role in cell division.  

Seckel syndrome is characterized by severe proportionally short stature with severe microcephaly, a ‘bird like’ profile include a receding forehead, large eyes, beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and mental retardation.  Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD) are both characterized by intrauterine growth retardation, dwarfism, and microcephaly.   MOPD is differentiated from Seckel syndrome by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Mutations in the PCNT gene have been described in many patients with MOPD or Seckel syndrome.  The PCNT gene is also thought to play a role in cell division.

Recently, Al Dosari, et al (2010) reported a homozygous splice site mutation, IVS11-1G>C, in the CENPJ gene in several members of a consanguineous family from Saudi Arabia with Seckel syndrome.  Mutations in CEP152 have also been identified in Turkish, Italian and South African families with Seckel syndrome.  Thus, it seems that MCPH, Seckel syndrome, and MOPD may all be part of a spectrum of disorders with a similar etiology.

We report molecular testing on a six year-old female with severe growth deficiency, microcephaly, developmental delay, and facial features resembling Seckel syndrome.  MRI of her brain is similar to that seen in patients with MCPH.  Full gene sequencing of CENPJ revealed a homozygous novel sequence change, IVS11-15A>G. In silico analysis using splice site prediction programs predicts that this sequence change creates a possible new splice acceptor site at the site of mutation.  Functional studies of this sequence change are pending. In addition, DNA from a subsequent affected pregnancy was also homozygous for this sequence change. It is interesting that our patient with a Seckel-like phenotype also had a possible splicing mutation in exon 11 of the CENPJ gene similar to the Seckel syndrome patients described by Al Dosari et al (2010) also with a splicing mutation affecting exon 11 of the CENPJ gene. It is possible that mutations affecting the splicing of this region of the CENPJ gene may result in more of a Seckel/MOPD phenotype than an MCPH phenotype. This patient illustrates the evolving clinical spectrum including MCPH, Seckel syndrome and MOPD.

This poster (#446) will be presented at the ACMG Annual Meeting by Melissa Dempsey,  our genetic counselor, Friday March 30: 10:30-11:30 am. Stop by and learn more.

We report a unique neurodegenerative disorder characterized by early-onset epilepsy, ataxia, progressive cognitive decline and retinitis pigmentosa (RP) in a highly consanguineous family of Pakistani origin. Affected members are three siblings including a 28-year-old male, 23-year-old female, and 15-year-old male, as well as their 30-year-old female cousin, clearly suggesting an autosomal recessive disorder. All affected individuals experienced a highly similar clinical course characterized by juvenile-onset seizures, retinitis pigmentosa and cognitive decline. Cerebellar signs manifesting as progressive ataxia and dysarthria appeared early and progressively increased, leading to severe impairment and confinement to wheelchair by early adulthood. Additionally, the older sibling experienced first-degree heart block and underwent pacemaker placement. Brain MRI of all affected individuals revealed severe cerebellar atrophy in the absence of cerebral atrophy or other structural brain abnormalities. Neuronal ceroid-lipofuscinosis (NCL) was suspected and investigated by histopathologic examination and electron microscopy (EM) studies of biopsied tissues, enzymatic analysis of PPT1 and TPP1 in white blood cells and molecular studies for the commonly implicated genes in NCL, which were negative. Hisopathologic examination and EM of rectal biopsy tissue revealed focal accumulation of lipofuscin bodies in ganglion cells and Schwann cells but no curvilinear or fingerprint bodies or excess accumulation of unstructured secondary lysosomes characteristic of NCL. Given these pathologic findings, the diagnosis of NCL was ruled out. Additionally, investigations for spinocerebellar ataxia, mitochondrial disorders, and congenital disorders of glycosylation have been negative to date.

In order to determine the molecular basis of the disorder in this family, whole genome sequencing has been initiated in conjunction with genetic linkage and homozygosity mapping.  Four affected individuals and three obligate carriers were used for the analysis.  Homozygosity mapping identified a single consensus region of homozygosity of ~6 MB mapping to chromosome 8 and containing 8 known RefSeq genes. Parametric linkage analysis revealed a maximum LOD score of 4.4615 (highly suggestive of linkage) within the region of homozygosity. Analysis and evaluation of the genes in this region is currently being performed, and these results, together with results of whole genome sequencing in this family will be presented.

This poster (#331) will be presented at the ACMG Annual Meeting by Ghayda Mirzaa, our molecular fellow, Thursday March 29: 10:30-11:30am. Stop by and learn more