Copy Number Variants – Benign or Pathogenic – a complex issue


Molecular cytogenetics offers the opportunity to recognize the smallest changes in the human karyotype. These methods show that the karyotype is not as stable as previously thought. Almost every person has small deletions or duplications, involving different areas of the genome. These small anomalies collectively are called copy number variants (CNV). These CNVs may involve one or several genes or may contain only gene-free areas of DNA. CNV may be sporadic or may be inherited. Currently all CNVs are divided into 3 groups:

  1. Benign CNV;
  2. CNVs of unknown (or uncertain) significance (VOUS);
  3. Pathogenic CNV.

Benign CNVs are mostly small (less than 0.2 Mb) deletions or small (less than 0.5 Mb) duplications, which do not include any genes or include genes, which do not cause any disorders. Most pathogenic CNVs are relatively large (more than 1 Mb) and include several genes. If any CNV is repeatedly found in association with a certain phenotype (for example, seizures or autism) such a CNV is considered as pathogenic. Deletions and duplications of chromosomes 15q13.3, 16p11.2, and 16p13.11 are examples of pathogenic CNV. VOUS are CNV, when it is not yet clear whether these variants are benign or may cause pathologic conditions. Further studies are necessary to reassign these CNV into “pathogenic” or “benign” classes.

In some families the same CNV which was found in a child with a clinical abnormality (for example, a heart defect or developmental delay) is found in one of his/her parents. Sometimes this parent is also affected (usually with milder clinical manifestations), but in most cases the carrier parent is absolutely healthy. It raises a question: how to explain that a child with a given CNV has some pathology, but his/her parent with the same CNV does not.

This explanation will be different for “benign” CNV and “pathogenic” CNVs. Benign CNVs are not related to any disorders. However, some authors just report all CNVs found in the specific group of patients (for example, patients with tetralogy of Fallot or cleft palate) but do not classify these CNVs into the sub-groups. The same situation may occur when a family considers a CNV found in a child as a cause of his/her disorder. Actually, however, if this CNV is benign it has no connection with child’s abnormality. It is evident that the same CNV may be found in a healthy parent. When a CNV is found in the examined child, all families have to ask whether this CNV is benign or pathogenic. If a CNV is benign we have to look for other explanations of the child’s disorder.

Explanations of the occurrence of a pathogenic CNV in a healthy parent are not so easy. To be honest, the nature of this phenomenon is not always clear. In most families, however, it is caused by participation of other genetic factors. The easiest example: assume that a healthy mother has a microdeletion of chromosome 16p13.11 involving the NDE1 gene, known to cause a severe autosomal-recessively inherited brain disorder. The non-deleted copy of this gene in this woman is normal. She transmits this deletion to her son. But if the healthy father of this child has a mutation in the same gene he can transmit the mutated copy to his son. In this case the child having a maternal CNV and a paternal mutated gene will develop an autosomal-recessive brain disorder. Several dozens of similar situations have been reported so far in the literature. But this explanation covers only a small fraction of cases where a healthy parent has the same CNV as his/her affected child. Another explanation presumes the influence of other genetic factors somehow controlling the expression of the pathogenic CNV. For example, small deletions 1q21.1 may produce a very serious condition – TAR syndrome (thrombocytopenia – absent radius) if the patient also inherits a small specific non-coding area of DNA. Sometimes regulatory genes may directly affect expression of the “critical” genes. And we cannot exclude the phenomenon of incomplete penetrance known in numerous dominant disorders, when a person having a mutant gene has no clinical manifestations. It is not clear yet whether some environmental factors may affect expression of CNVs.

CNV is a relatively new topic in human cytogenetics, and there are many white spots regarding the role of these microdeletions and microduplications in humans.

Is it reasonable to test small brothers and sisters of the child with pathogenic CNV if this CNV is inherited from the healthy parent? The results of the test will not change health of the child but (if the test is positive) may add a psychological burden. When the child reaches child-bearing age this testing may become more reasonable, especially if we know not only the possible clinical consequences of the given CNV, but also know the proportion of the affected persons among all carriers of the given CNV.

Dr. Iosif Lurie, Medical Geneticist, CDO Medical Consultant

CDO’s 15 Giving Days AND 15 Giving Ways


CDO’s 15 Days of Giving AND CDO’s 15 Ways of Giving

Chromosome disorders may affect 1 in 150 individuals.

Help CDO to always be there for those affected and their families by supporting our 15 Days of Giving Campaign.  Together we can do it!

1. CDO manages a Facebook group so members can share pictures, stories, and questions!
2. CDO offers personalized networking programs.  We work hard to match members with those who have the same or similar disorders, share medical conditions, and live in the same region.
3. The CDO Ask the Doctor service is available to all website visitors.
4. CDO maintains a library containing thousands of articles – we add up to 50 new articles monthly .
5. CDO employs consulting geneticists who answer personal inquiries and make referrals to additional resources.
6. CDO publishes a periodic newsletter.
7. CDO archives several years’ worth of newsletter issues that may be downloaded on demand from each member’s private CDO account.
8. CDO maintains an interactive website and is continually adding new resources to further help individuals and their families.
9. CDO offers personalized research services.
10. CDO monitors a telephone helpline 561.395.4252
11. CDO keeps a detailed database registry including medical and developmental symptoms allowing us to provide very real data (de-identified) to researchers
12. CDO raises awareness through Rare Chromosome Disorder Awareness Week each June.
13. CDO creates a calendar of member artwork and photos every holiday season… highlighting the beautiful faces and the beautiful creations of these members.
14. CDO operates an online store to help raise awareness.
15. And most importantly… For 25 years CDO’s many programs have ensured that individuals and their families know they are never alone. Whether this diagnosis is received prenatally or when a patient is an adult – CDO will always be there to help.


Recognizing Potential & Beauty: The Story of Emily – By Kathy Paulsen


When I received my daughter Emily’s diagnosis of a chromosome 5 long-arm deletion nearly 20 years ago, access to information regarding disabilities was minimal. There was no Internet. We had no personal computer. I received one very bleak case study from the genetic counselor, and was told, “She’s still the same person, take her home and love her.”

Of course I did that, but I struggled to do more as the doctor’s words “mental retardation” and “early intervention” echoed in my head. I was desperate for information, for compatriots in this foreign
community, for predictions of what my daughter’s life would be like. My lifeline was my CDO newsletter and parent network. I later discovered Unique, and I subscribed to Exceptional Parent magazine. I received some valuable information, but nowhere did I find a child just like mine. I found myself constantly trying to explain to others what I didn’t even understand myself.

I wish then there had been the uplifting and relatable stories of The Mighty back then, the ability to Google her conditions and to find a few others like her in a Facebook group.  I would have loved to have others’ online cheers for her inchstone successes, and to commiserate over the unique sorrows we faced. It is wonderful that those resources exist today. But she is still rare among the rare. Getting early services was easy, the needs of my verbal but largely unintelligible daughter clear. At 3, she had the developmental abilities of an 18 month old. I was warned that she would likely never learn to read. She started in a pre-primary impaired preschool and received speech, occupational, and physical therapy. I had some guidance and some support. The cloud was lifting.

As we fell into our “new normal,” life became happy again. My initial quest for answers softened into a day-at-a-time perspective. With the help of some excellent teachers and professionals, I could once again have mom as my primary role, putting educator and therapist secondary. And I realized that no child arrives with his or her fortunes foretold. So I could let go of trying to figure out Emily’s future, feel more content with the knowledge that we would be there to give her what she needs, when she needs it. I learned to let Emily be my guide for many things. I learned, as parents do with all children as they raise them, to interpret her body language and temperament. With her clues, I could avoid most crises and melt-downs. She knew more than anyone what she could do. My role was to coax and encourage, watch and listen.

There were, however, battles. Battles with insurance companies, with school personnel, and yes with my husband and with myself. Battles to get people to listen to information about a disability that has no syndrome name. Battles to be seen as the authority on Emily by the doctors charged with treating her. Battles to get school administrators to address bullying. Battles within myself to ignore the judgments thrown our way from friends and strangers alike when they would witness things they did not understand, and to figure out when to respond or explain. Battles to answer questions with elusive answers: what surgeries and treatments, what therapies, am I doing too little or too much, how much do we push her academically? Socially? Physically? How do I keep her identity and mine separate when our lives are so entwined? And the biggie now: How do I help people understand that disabled and capable are not mutually exclusive?

As we begin the journey to navigate Emily’s life as an adult, the lack of clarity persists. Organizations and individuals want proper labels for her, but they don’t exist. Maybe it’s a human tendency, to create neat categories to put folks into? Emily doesn’t fit into any easy category and never has. She did indeed learn to read. It took 6 years, but she hasn’t stopped since. Against all odds, she finished high school with a true diploma and now attends classes at community college. She delights in working with the 3 year olds at the Easter Seals preschool where she volunteers. She enthusiastically cheers for her Special Olympics swim teammates and gives her all to the sport. She has gifts and talents and loves putting them to use. She has a heart and soul that inspires all of us who know her to be better people. She has persistence and perseverance, creativity and kindness. But she also needs help crossing the street safely, buttering a piece of bread, and brushing her hair. She has very serious medical issues and real disabilities including developmental, vision and speech impairments.

I still struggle with how to explain her chromosome deletion to new people. Maybe that’s better. If I had a tidy label that people widely understood, in their own way, it would not tell the whole story of who she is. I would name the condition and people would think that’s her. It’s not. Not for anyone. We are each a messy array of personality traits, strengths and weaknesses, abilities and deficits. This array is impossible to fully discern from outward appearance or generalized category. Perhaps this understanding is one of Emily’s greatest gifts to me, recognizing potential and beauty in every individual.

10 Ways to Celebrate Rare Chromosome Disorder Awareness Week


PURCHASE and wear with pride your new RCDAW t-shirt.

ORGANIZE a RCDAW event. The event organizer and their child receive free t-shirts. The event could be a “dress down for a dollar” day, bake sale, dine-around at a local restaurant (portion of proceeds to CDO), or something else.

PARTICIPATE in CDO’s sibling poetry contest. Send poems (with first name and age of author) to or post on our Facebook page. Winner receives a RCDAW t-shirt.

CUSTOMIZE the new RCDAW logo to include your child’s picture.

VISIT the CDO website for all the latest information and news…

SHARE the CDO link with Facebook friends and Twitter followers.

READ a book to your child that celebrates everyone… for example, Special People Special Ways by Arlene Maguire.

WRITE a letter to your congressperson expressing your support for the 21st Century Cures Act.

POST on Facebook or send a Tweet every day for the week describing how your child with a chromosome disorder is courageous, determined, optimistic, and more.

EMAIL information and a photo of your child to CDO at (diagnosis, likes, daily accomplishments, etc.). We will feature several children each day on Facebook, Instagram and Twitter during the week of June 7-13.

Chromosome Disorder Outreach Inc. is a non-profit organization providing information and support to all those coping with a rare chromosome disorder diagnosis.  Whether this diagnosis is received prenatally or as an adult, CDO will always be there to help.


Smooth Surgery

Comforting your child at the hospital is never fun. However, there are some vital steps that can make it more relaxing and more effective for both you and your child.   You can bring familiar items with you, create a peaceful environment before and after surgery, and calm yourself.

The most frightening thing seems to be the unknown. I know my daughter was far more upset by her first few surgeries than she is now. The hospital has become familiar. The staff remembers us and we remember them. We kid that we are just trying to get enough “frequent flyer” miles from the hospital to earn the trip to Hawaii. I always talk to my daughter about the surgery. I remind her of the waiting room and the beds and the funny gown she gets to wear. I talk to her about the elevator rides and how I’ll be waiting for her. I try to remind her it’s going to be fine, just like the last time and the time before that and the one before that.

When my daughter was preregistered for her first surgery, the nurse asked if there was anything that brought her comfort. The only thing I could think of was me. As she has gotten older, and tolerates more sensory stimuli, she has adopted a favorite blanket. That always goes with us for surgery now. My daughter also loves music. When we pack for surgery, I make sure my phone is charged and that I pack a charger. That way I can make sure to have music for her. If we end of being admitted after surgery, I have several cd’s that I take, as each room in our pediatric wing has a cd player.

I also pack some of her favorite home “smells.” I love to have peppermint essential oil scenting my home. It’s a smell my daughter is very accustomed to. For that reason, I pack some essential oil blended into fractionated coconut oil. I rub that on my hands. Then as we snuggle, she feels more at home.   As with all essential oils, I take care not to rub it in her eyes or my own eyes.

When surgery is scheduled, I try to get one of the first appointments of the day. This allows for my daughter to fast while she is sleeping. It also helps with time management. We don’t end up waiting in the waiting room forever while doctors attempt to hurry with other procedures that have gone longer than planned. Her doctors are also more rested and refreshed. The waiting room is not as crowded, which allows us to have a little more breathing room and a little less stress.

Once my daughter has been taken back to the operating room, I usually put my headphones in. Just because you are wearing headphones doesn’t mean you have to listen to them. I usually do listen to my calming play list, but sometimes I just want that separation from the other people in the room. It allows me to rest a bit without having to answer questions from others. I usually can’t read a book, but a frivolous magazine comes in handy. I also like to play Sudoku on my phone because it forces me to concentrate on the numbers and not on what is happening with my daughter at that particular moment.

The most important thing I do during this time is to find a way to relax. I know that relaxing is extremely hard to do in this setting, but it is vital. As soon as surgery is over, and my daughter goes to recovery, I will need to be calm and able to hold her, sing to her, and make her feel better. I can’t do that if I am completely frazzled.

When I finally get to be with my daughter, I usually hold her in my arms. She is four years old, but very small.   She loves to be held in a particular way, so I hold her just that way. I ask for pillows to put under my arms so that I can hold her there as long as needs be.   I also sing to her. I don’t care that my voice is not that great, nor do I care what the nurses think. My girl likes me to sing to her, so I do.

The most important thing to remember is not to freak out. If they had to try five times to get her IV in and my daughter is covered with bandages from that and bruised to boot, I can be angry later. If she throws up all over me as she is coming out of the anesthesia, I clean myself up and snuggle her more. If she screams like a banshee and cries great big alligator tears, it breaks my heart. But, I have to keep myself calm so that she doesn’t pick up my stress and get more agitated.

I try to maintain this calm composure throughout the remainder of the day.   I utilize my hospital’s valet parking to help us arrive and leave. If I haven’t eaten, I pick up lunch, via drive through, on the way home. I usually put dinner in the crock pot early in the morning, pull out a freezer meal or order pizza for the family.   I don’t worry about the daily cleaning that isn’t getting done. It can wait. We all wear our comfy pj’s and watch silly old movies for the rest of the day.

The most important part of helping your child is to be calm yourself. Help them get familiar with the hospital. If they haven’t had surgery there before, take them to the hospital. Show them the waiting room. Help them meet some of the staff. Let them ride in the elevators. The day of the surgery, take familiar items with you. Remember that all of their senses may need to be calmed.   If your child likes to be massaged, remember to do that. If they can’t stand their feet rubbed, don’t rub them! Remember to calm yourself. Take deep breaths. Eat a snack. Stay hydrated. Talk to a friend. Both you and your child will feel much better about the day if you go about it calmly.

Submitted by: Kori Lester



Surgery from a Parent’s Point of View by Meshell LaBaun

You have been told by one of your child’s doctors that surgery is recommended to resolve an issue, what do you do now? In my experience this recommendation was never unexpected. My son was diagnosed with club feet prior to birth, I had weeks of preparation for his birth and knew that he would be placed in casts within a week after hospital discharge and a few months later he would have an outpatient surgery.

Of course life did not happen that perfectly. We had other medical issues which delayed discharge and the outpatient surgery ended up being an overnight, but I still knew it was coming. A few years later I asked his orthopedic surgeon if surgery was necessary again; she asked if we ever suspected a tethered spinal cord. The following week we were scheduled for his third spinal MRI after which, spinal surgery was recommended. We had been researching the pros and cons of spinal surgery for months so, again, it was not a surprise. A few months later we did need foot surgery again, as a mom I knew his feet were not correcting well. A year later I called the orthopedic surgeon to up our appointment, the feet were not right again, I was concerned surgery was the only option…I was right.

You know your child better than any of the doctors so learn to teach the doctors about your child because in many cases they may never see a child like yours again and you have the ability to truly express how great, fantastic and unique your child is. If you think surgery may be an option, inform the doctor, ask their opinion, ask another doctor if you want and then think of all the pros and cons regarding the surgery and make an informed decision. If a doctor does mention surgery and you are not prepared for this option to let them know you would like more information, a second opinion or at least some time to think about it. Unless the surgery is an emergency you have the right to take some time to prepare yourself and your child.

Typically you are given a few weeks’ notice before the surgery in planned, I tend to call the doctor to speed up scheduling. Take this time to familiarize yourself and your child to the hospital and the expectations of the day. My son is still young and not as aware as an older child but he does have an older brother so I take the time to explain to my other child what his little brother will have happen, how his daily schedule may be changed and why we are doing surgery. Let family know and if you want their assistance see who may be able to help. For our family we notify my younger son’s daycare staff, my older son’s teacher (to give her warning in advance for anxious behavior on his part), our places of employment and family. We ask the doctor when he will be clear for daycare so my husband and I can take the appropriate amount of time off work. We consider and ask advice on how to handle issues such as bathing, riding in a car seat, sitting chairs, sleeping to ensure that we are prepared to handle post-surgery care (which involves casts for us a lot of the time). See if it is possible to preregister for surgery by either calling the hospital or online, this can save you time the morning of the surgery. Make a list of things to take to the hospital both for yourself and for your child and ensure that the hospital does not have any restrictions. I am packing snacks, drinks and something to read for myself and books, toys, a sippy cup and snacks for my son. Don’t forget to pack any medications your child takes.

The night before surgery make note of when you are to stop giving your child food as well as when you have to hold off on clear liquids.   If you have to travel to a destination you are not familiar with review the path and give yourself plenty of time to arrive to the hospital. You may also review the hospital’s website for information on what to expect, some children’s hospitals have videos the kids can watch so they know what to expect that day.   Ensure your bag is packed and you have medications, insurance information and identification for your visit. Be as calm as you can to help reduce your child’s anxiety and everyone should get a good night sleep.

When you arrive at the hospital you may need to check in and finish registration, this is when you will supply insurance information and your identification and sign documents. Your child will be given an identification tag and you will have a choice as to where it goes, my son loves to chew anything so if possible we had it placed on his legs, if he was going to receive leg casts of course we had it go on his arm. Any issues with billing or parking should be discussed at this point in your visit. Next you may be directed to surgical waiting, or you may go directly here to check in until the staff is ready to take you and your child back to pre-op, there may be a limit to the number of visitors that go back so check with hospital staff before you arrive with family in tow. In pre-op is where you will meet anesthesiologist, nurses, doctors, etc , who are there to help you and your child as well as prepare your child for surgery.

If it is a teaching hospital, like the one we go to, you will typically meet two of each type of staff. The resident comes in first then the attending staff later. Help the hospital staff by informing them of what makes your child unique, they will ask a lot of history questions and do your best to answer questions and if a procedure was done in the hospital prior ensure they know to review prior notes. Items I have brought to the attention of staff are:

  • Ability for my son to get things off his hands (important for ID bracelets and IV lines)
  • Past difficulties with anesthesia
  • Ability to use a cup, sippy cup, or bottle and what drinks he dislikes (this is important for after surgery)
  • My son’s personality around strangers


As I said before you know your child the best so think about what is most important for someone to know about your child when you are not around and let them know how to best care for your child while they are in the hospital staffs care.

After your child goes into the operating room you will be directed to return to the waiting area and be told not to leave. Some people bring most of their family, others have just a spouse or perhaps another child, some are like me and sit alone. Each person knows how they can best deal with the situation and how they are most comfortable. I typically bring something to read and a few snacks so I don’t need to even run to the vending machine. If you do need to leave the room and you are alone inform a staff member that you are leaving and insure they have your child’s name and yours written down, if you have a cell phone give them your cell phone number so in the event that the doctor needs to speak to you they can reach you even in the restroom. If you wish updates on your child’s progress you may be able to ask the staff to check on it, sometimes a message will be given to you periodically, especially if it is a long surgery.

When your child is out of surgery you will be notified and will have an opportunity to speak to the doctor. Sometimes this is a quick chat in the waiting area, sometimes it is over the phone, other times you are escorted to a conference room. These are doctor preferences and do not mean the conversation is bad or good news and I am sure if you requested a personal conference room the doctor would grant that request. If surgery is outpatient, you will be able to go back to recovery once your child has awakened and had something to drink to sit with them while the anesthesia wears off. If your child’s surgery requires an overnight stay you may be given the room number and be asked to proceed to the room and your child will meet you there shortly. Remember that you are on hospital time and shortly means as soon as we feel your child is well enough to be moved and could be an hour or more.

If you are having same day surgery, stay as long as you feel is necessary in the recovery room. Ask nurses as many questions as you can think of to ensure that you will know what to expect at home and when a call to the hospital or your doctor is warranted. For an overnight stay understand that you will most likely get little to no sleep, my son is notorious for getting wires moved and causing his monitors to beep hourly or more frequently. Know when shift changes are so you can ensure you are in the room to meet the next nurse, ask if they have any questions as many nurses are curious about what brought you to the hospital and what you hope to gain from the surgery. Know where to get food for yourself and if you have to leave your child alone stop by the nurses’ station to let them know you will be back shortly. Know your child’s medications and their individual schedules, some like antibiotics require strict doses, others such as pain medications typically are as needed at least so many hours apart. If you don’t think your child needs pain medicine on schedule ask if it can be delayed. If you feel your child is not being helped by the pain medicine, let your nurse know so they can ask about alternatives. You know your child and how they show pain.

When you come home with your child make any adaptations necessary, ensure you have their medication on hand and know the dose schedule and make any follow up appointments with their doctor. Recovery does not end when you leave the hospital but you may be surprised at how quickly your child returns to their old self.


Submitted by: Meshell LaBaun


Applying for Social Security Disability with a Chromosomal Disorder

Applying for Social Security Disability with a Chromosomal Disorder

When it comes to finances, oftentimes people living with a disability need extra help, especially those living with a chromosomal disorder that will affect them for the entirety of their lives. The United States government encourages people with a disability to apply for Social Security Disability benefits. The monthly payments and medical benefits that the disability programs offer can greatly help their financial burdens.


What is Social Security Disability?

 The government has two different programs that can help people with a disability. The Social Security Disability Insurance program, also known as SSDI, pays benefits to people that have worked and paid social security taxes in the past. This program mostly helps individuals that have worked and paid Social Security taxes for a certain period of time and before becoming disabled. The Supplemental Security Income program, also known as SSI, is designed to help those that have little or no income and lack a sufficient work history.


Technical and Medical Requirements

 Individuals looking to apply for Social Security Disability benefits must meet certain requirements. When applying for SSDI, you must meet work history and medical eligibility requirements. On the other hand, to qualify for SSI, you must only meet the medical and income requirements and asset limits.

A person’s work history determines whether or not a person is eligible to receive Social Security Disability benefits. In order to qualify for SSDI, the applicant needs to have earned enough work credits, meaning you paid Social Security taxes, depending on your age. Work credits are earned each year that you work, and a worker can earn up to a maximum of four work credits per year.

To be eligible for SSI benefits, your household income can’t exceed $761 as an individual or $1,082 as an adult. Your household assets also can’t exceed $2,000 as an individual or $3,000 as a couple.

In addition to meeting the technical requirements of the SSI and SSDI programs, you also need to meet the medical criteria. The SSA published the “Blue Book”, which lists all of the disabling conditions that could qualify you for benefits. Each condition has its own set of criteria that must be met in order to prove that your condition is in fact disabling.

Chromosomal disorders are covered under Sections 10.00 (adult listing) and 110.00 (child listing) of the SSA’s Blue Book. In order to be approved for disability benefits under this section, you must be able to provide the SSA with clear evidence of:


  • A diagnosis;
  • A copy of a laboratory report of a conclusive karyotype analysis;
  • Medical records showing physical manifestations of the condition are present; and
  • Evidence that your condition interferes with your ability to function.


Applying for Social Security Disability

You can apply for Social Security Disability benefits online or in person at your local Social Security office. Applications for children must be filed in person at an office. If applying in person, you should call the SSA’s toll-free number at 1-800-772-1213 to make an appointment with the local Social Security office. This option also allows you to make an appointment to apply for Social Security Disability over the phone. Once a disability appointment has been made, you will be sent a disability starter kit in order to prepare for the interview.


What Is Needed to Apply

 When starting the application process, you will need the following information:

  • Social security number
  • Copy of the birth certificate
  • Names, addresses, and phone numbers of the doctors or hospitals that addressed the disability.
  • Complete medical record of all visits associated with disability.
  • Laboratory and test results.
  • Summary of work and the type of work completed.
  • Copy of the most recent W-2 form.

In addition to this information and the basic application, applicants will need to fill out other forms. One form will describe the medical condition and how it affects the applicant’s ability to work; the other form simply gives health care professionals the authorization to give out personal medical information.


Benefits after Approval or Denial

 Once the disability application is approved, you can expect to receive a monthly payment to help cover basic needs of living. This notice will be received two to four months after the date of the initial application. If the claim was denied, you have 60 days to appeal that denial from the date of the notice. A good number of applicants may be denied during the initial stage of the application process, but are awarded benefits as the result of an appeal.

Considering Legal Representation

 Although there’s not always a need for legal representation during the application process, having a lawyer’s help can greatly improve your ability to be approved for disability benefits. A lawyer will know how to handle all situations and can correctly fill out all necessary forms. As an expert in the field, a lawyer knows what laws affect your particular disability case and will be able to put those laws to work for you.


Lisa Giorgetti
Community Liaison
Social Security Disability Help

Perspectives for Treatment of Chromosome Disorders


Chromosomal disorders are conditions where, as a result of deletions or
duplications of some chromosomal segments, the organism experiences the excess or absence of a significant number of genes. Manifestations of chromosomal disorders include both morphological defects caused by the abnormal action of genes during embryonal development and functional abnormalities (seizures, hypotonia, aggression, hyperactivity, sleep disturbances, etc.) caused by the constant abnormal action of genes. When we use the term “treatment of chromosomal disorders” we talk about attempts to alleviate functional abnormalities and give patients a better chance to live independently. It is obvious, however, that morphological defects which occur during embryonal development cannot be restored by any drugs.

The existing attempts for treatment of patients with chromosomal
abnormalities may be subdivided into several groups. The potentially most fundamental methods have a goal to restore a normal karyotype or inactivate the action of excessive genes. One strategy involves inactivation of one of the chromosomes 21 in a trisomic patient with Down syndrome. One of the human genes – gene XIST –
inactivates one of X-chromosomes in females. The XIST gene prevents
transcription of the genes on the X-chromosome. If this gene is inserted into one of chromosomes 21 in a patient with Down syndrome, this chromosome will became inactivated, restoring the normal “disomic” condition. Currently the experiments with inactivation of excessive chromosomes are in the “embryonal” stage; if these tests provide good results in laboratory animals, this method will be tested with clinical trials. Although currently XIST-strategy is studied only for
cells with trisomy 21, the same method may be promising for other trisomies as well.

Some types of chromosomal pathology (ring chromosomes, additional
markers, dicentric chromosomes) are relatively unstable. Most patients with these abnormalities have both a clone with an abnormal chromosome and a normal clone. Generation of pluripotent stem cells from the skin cells of a patient with ring chromosome 17 has shown that reprogrammed cells lost the abnormal chromosome 17 and duplicated the wild-cell normal homologue. If this is true for other ring chromosomes and other forms of “unstable” pathology, it will provide an
opportunity to use cellular reprogramming as a way of therapy for certain chromosomal disorders.

A strategy of reprogramming as well as XIST-strategy, however, will (or
may) cause uniparental disomy – a condition when both homologues chromosomes are identical (i.e. two copies of the same maternal or paternal chromosome). If this chromosome carries an autosomal-recessive gene, the patient (or reprogrammed cells of the patient) may become homozygous for this gene.

Other methods for treatment of chromosomal pathology seem to be not so fundamental by nature but more achievable. Down syndrome for instance is a condition where several attempts for treatment of patients with this pathology have been made.

It is well known that the size of the cerebellum in persons with trisomy 21 is significantly less than in persons with a normal karyotype. As a result there is a considerable impairment of cerebellar function in patients with Down syndrome. In the experiments with a specific line of mice Ts65Dn (widely used as an animal model of Down syndrome) the newborn animals who received a stimulation by “Sonic hedgehog” – a growth factor involved in different aspects of development -show both an increase of the size of cerebellum and an improvement of its function. Mice “treated” by “Sonic hedgehog” show an ability to learn their way around a maze – an indicator of function of learning and memory. The idea of early intervention seems very plausible, but there is still a long way to go between experiments with rodents and the clinical usage of “Sonic hedgehog” (or other growth factors) in treatment of Down syndrome.

Experiments with the mice Ts65Dn show that these animals demonstrated excessive inhibitory brain activity. Release of this inhibitory effect may improve cognitive function. One way to reduce this inhibitory effect is to block the activity of GABA – the primary inhibitory neurotransmitter. There are experiments where
Ts65Dn mice were chronically treated with a negative allosteric modulator of GABA RO4938581.

It has been shown that this treatment improves the functional and neuromorphological deficit in a mouse model of Down syndrome. Currently there are some clinical trials ongoing to test this kind of treatment in adult patients with Down syndrome.

An examination of the brains in Down syndrome patients has shown a remarkable similarity between these brains and those in persons with
Alzheimer syndrome. Most Down syndrome patients develop Alzheimer-like plaques and dementia in their 40s. Persons with Down syndrome have high levels of myoinositol – a chemical related to cognitive impairment and involved in formation of plaques in the brain. There is a trial to treat patients with Down syndrome by scyllo-inositol (ELND005) – a drug originally synthesized to break up amyloid plaques in the brains of patients with Alzheimer’s syndrome. The current trial hopes to demonstrate the efficacy of this method for treatment of Down syndrome patients.

There are some publications describing possibility of “pathogenetic”
treatment in other conditions. For example many manifestations of Phelan-McDermid syndrome (deletion of 22q13.3) are caused by the loss of SHANK3 gene, which resides in this area. Neurons of Phelan-McDermid syndrome patients have reduced SHANK3 expression and defects in excitatory, but not inhibitory, synaptic transmission. Treatment of the neurons with insulin-like growth factor I (IGF1) corrects the excitatory function of these cells and shows the pathway to
correct intellectual disability and speech impairment in patients with this disorder.

The more common and more standard ways for treating chromosomal
disorders are related to the replacement of products which are not synthesized in a patient or synthesized at an unusually low level. It is similar to the usage of insulin in patients with diabetes. For example, patients with Klinefelter syndrome have very low levels of testosterone. The administration of testosterone in adolescents with Klinefelter syndrome shows good clinical efficacy in 95% of patients.
Patients with distal deletions of the long arm of chromosome 15 usually reveal significant growth delay, because this deletion involves the gene responsible for synthesis of the growth hormone. The administration of growth hormone significantly improves the growth in these patients. Treatment by growth hormone may be beneficial also for other patients with other chromosomal pathologies experiencing growth delay.

Common drugs for treatment of attention deficit hyperactivity disorder or seizures may be used also for the treatment of these manifestations in patients with chromosomal pathology, although clinical results may vary even in persons with the same chromosomal imbalance.

Dr. Iosif Lurie
Medical Geneticist
CDO Consulting Medical Advisor

Are Rare Chromosome Disorders Really All That Rare


Chromosome disorders: 2014 outlook

The whole concept of chromosomal disorders has drastically changed in the last several years. Traditionally, the examination of chromosomes under the microscope was the main (or even the only) way of diagnosing chromosomal pathology. However, even in optimal variants visual examination allows recognition of deletions or duplications not less than 5 Mb. Actually, the vast majority of patients recognized as having chromosomal anomalies had an excess of deficit of very large segments of DNA (at least 10-15 Mb). Of course, such large segments contain dozen of genes – including genes involved in mental development and numerous morphogenetic processes. Virtually all persons with unbalanced chromosomal abnormalities recognized by a “standard” cytogenetics had delayed psycho-motor development, facial dysmorphism and (in many cases) defects of the brain, eyes, heart and other organs. As a result, chromosomal disorders were considered conditions involving (as mandatory traits) dysmorphic features and delay in psycho-motor development.

Methods of molecular cytogenetics which have become a common practice over the last few years allow recognition of even the smallest imbalances. As a result it has been found that a large number of patients previously reported as having a normal karyotype, actually have small deletions or duplications. Contemporary data shows that ~25% of persons with facial dysmorphism and a various degree of psycho-motor delay have deletions or duplications of chromosomal material. Only one third of these abnormalities could have been diagnosed by “standard” cytogenetic examination.

It has been shown that several syndromes of “unknown” etiology actually are caused by small chromosomal imbalances (Williams syndrome is caused by 1.5-2 Mb deletion of 7q11.23, TAR syndrome is caused by proximal del 1q21.1). Many other syndromes can be considered as etiologically heterogeneous: in some cases these conditions are caused by a mutation of one gene, in other cases by microdeletions involving the causative genes. It may be true for Sotos syndrome, where many patients have del 5q35, for Rokitansky-Küster syndrome in patients with del 17q12, etc. Numerous new syndromes caused by chromosomal microdeletions or microduplications have been delineated over the last 4-5 years (del 1p34, del 2p15p16, del 17q21.31, etc.). These new syndromes involve all chromosomes and almost all segments of DNA. In all these conditions there are no doubts about the pathological role of the given deletion or duplication.

Molecular cytogenetics has shown that above evidently pathological microdeletions and microduplications there are 3 other classes of microanomalies: a) “presumably pathogenic” copy number variants (CNV); b) benign CNV, and c) variants of unknown significance (VOUS).

Examination of a large group of persons has shown that several forms of microdeletions and microduplications (del/dup 15q11, del/dup 15q13, del/dup 16p11, del 16p13) are relatively common and may be found even in healthy persons. However among patients with clinical abnormalities which do not seem to be characteristic for traditional “chromosomal disorders” (e.g., in patients with autism or epilepsy) these CNV have been discovered much more commonly (sometimes 10 times more commonly) than in general population. There is doubt that these variants strongly predispose to some forms of pathology although the mechanisms of the realization of these effects are not fully explained.

Special examinations has shown that up to 8% of patients with epilepsy, 6% persons with autism and 2-3% of persons with schizophrenia may have copy number variants as causative factors of afore-mentioned conditions. Epilepsy, autism and schizophrenia are very common disorders. Even if only 2-3% of the patients with these conditions are caused by chromosomal rearrangements it will considerably increase the general pool of persons with rare chromosomal disorders.

An increased frequency of copy number variants was found among persons with different forms of heart defects (tetralogy of Fallot, stenosis of pulmonary artery), among patients with cryptogenic cerebral palsy (cerebral palsy without evident acquired cause) and even among obese persons. All these facts lead to significant expansion of the general pool of “rare chromosomal anomalies”. Of course, these calculations include only definitely pathogenic or presumably pathogenic CNV. And neither developmental delay nor dysmorphism seem to be mandatory for disorders caused by excess or deficiency of chromosomal material.

If any given variant occurs in affected and healthy persons with the same frequency this variant should be considered as benign.

The largest problem is variants of unknown significance (VOUS) when (at least currently) it is not possible to determine significance of the found variant. Several factors should be considered upon analysis of each such variant.

  •   Character of the lost (or added) genes. If the list of abnormal genes includes genes known to be related to human disorders, the variant is likely pathologic. If the given variant does not involve any genes, it almost certainly has to be considered as benign.
  •   Type of variant – a deletion of the same size is ~ twice more likely to be pathologic than a duplication of the same size.
  •   Size of deletion (or duplication) – basically the larger size presumes involvement of a larger number of genes.
  •   Inheritance of the variant: the variants inherited from healthy parents are most likely benign variants, whereas sporadic deletions (or duplications) are more likely to be pathologic.

    Although the list of VOUS is shrinking (some variants became considered as benign and vice versa), the large number of VOUS remains a significant obstacle in interpretation of data obtained by molecular cytogenetics.


Dr. Iosif Lurie, Medical Geneticist, CDO Consulting Medical Advisor