Tag Archives: #raregeneticdiseases

Wilson Disease

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, CIO Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Wilson Disease is caused by mutations in the ATP7B gene on chromosome 13q14.3.

Over 500 mutations in this gene have been described. The disease is quite variable with onset commonly between 5-35 years.  Incomplete penetrance or possible gene modifiers have been suggested for the variable presentation. 

Symptoms include:

  • Decreased appetite
  • Fatigue
  • Abdominal pain
  • Kayser Fleischer Rings (brown discoloration of eyes)
  • Speech or swallowing problems
  • Coordination difficulty or uncontrolled movements
  • Liver, kidney, psychological and/or neurologic problems
  • Anemia
  • Jaundice

Untreated liver failure can necessitate liver transplantation.

It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Wilson Disease) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background. With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required. 

Cohen Syndrome

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, CIO Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Cohen Syndrome also called Pepper Syndrome is caused by a mutation in the COH1 gene also called the VPS13B gene for the Vascular Protein Sorting 13B gene on chromosome 8q22-q23. 

Over 100 mutations have been identified in the gene. The syndrome is more common in the Finnish, Amish, Greek, Mediterranean and Irish population

Cohen Syndrome has its onset at approximately age 5 years and often shows progression between ages 7-14 years. Symptoms include:

  • Neutropenia (low white blood cell count)
  • Hypotonia (low muscle tone)
  • Feeding and speech problems
  • Developmental delay
  • Progressive vision loss

Cohen Syndrome is inherited in an autosomal recessive manner. Carriers are usually asymptomatic.

It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Cohen Syndrome) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?

If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background. With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required. 

Deafness – Treacher Collins

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Treacher Collins Syndrome – Mandibulofacial Dystosis) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) mutation from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background.

With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

It can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

Treacher Collins Syndrome is very variable and can have multiple medical problems.

Case Study A 28 year old female with classical Treacher Collins Syndrome, diagnosed clinically as a child, presented in early pregnancy with multiple issues, not all of which were related to Treacher Collins Syndrome.

The patient’s medical problems included:

  • Complex partial seizures
  • GI dysregulation
  • Common variable immune deficiency (CVID)
  • Rheumatoid arthritis
  • Hearing problems

Treacher Collins Syndrome is most commonly inherited in an autosomal dominant manner but autosomal recessive inheritance (25% if both parents are gene carriers) has also been described. 40-50% of Treacher Collins Syndrome cases are due to a new mutation. The severity of an autosomal dominant disease can be very variable from individual to individual even within the family.

The prevalence of Treacher Collins Syndrome is approximately 1 in 40,000 to 1 in 70,000.Ultrasound Diagnosis for fetal Treacher Collins Syndrome may be difficult. Findings can be variable and may include:

  • *Polyhydramnios
  • Small jaw (micrognathia)
  • Malar hypoplasia
  • Low set or abnormal ears.
  • Cleft lip and/or cleft palate

*Polyhydramnios can be a possible indication for fetal swallowing difficulties and delivery can be accompanied by moderate to severe fetal airway obstruction.

The most likely reason for a Treacher Collins Syndrome diagnosis is a new mutation in the TCOF1 gene on chromosome 5q32-33 which is inherited in an autosomal dominant manner.

This could place all of the patient’s children at a 50% risk for inheriting the deleterious mutation.

Mutations in the POLR1C gene on chromosome 6p21.1 can cause the syndrome and can be inherited in an autosomal dominant or autosomal recessive manner.

Rarely, mutations in the POLR1D gene on chromosome 13q12.2 may also cause a similar syndrome and is inherited in an autosomal recessive manner. Individuals with this syndrome will have inherited one deleterious mutation from each carrier parent.

Because the severity of the syndrome, if present, cannot be diagnosed by mutational analysis, a patient may wish to rely on ultrasound findings and routine prenatal testing to evaluate fetal well-being or fetal risk.

If a patient’s mutational analysis for PCOF1 returns as positive, prenatal diagnosis by amniocentesis is a possibility.  

Whistling Face Syndrome

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, CIO – Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Whistling Face Syndrome (Freeman-Sheldon Syndrome) is a rare disorder involving muscles which has also been called Distal Arthrogryposis .  The disorder usually involves at least two or more body areas with contractures of the hands and feet being common.

Whistling Face Syndrome may be sporadic or can be inherited in an autosomal dominant (50%) and autosomal recessive manner (25% if both parents are gene carriers).

One of the characteristics of autosomal dominant disorders which is due to the inheritance of one deleterious mutation in a gene is variable penetrance and variable expression. This means that the disease can be very variable from very mild (which might even suggest that the deleterious gene is not present) to more severe than the parent’s condition.

Other manifestations of Whistling Face Syndrome can include:

  • Craniofacial abnormalities
  • Spinal abnormalities
  • Small mouth
  • Pursed lips
  • Prominent cheeks
  • “Whistling” facial appearance
  • Small jaw
  • Flattened midface
  • High arched palate
  • Small tongue

Mutations in the MYH3 gene on chromosome 17p13.1 may be identified in up to 99% of individuals with Whistling Face Syndrome.

It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Whistling Face Syndrome) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

Resources:http://www.faces-cranio.org/Disord/Freeman.htm

Distal Arthrogryposis

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, CIO – Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Distal Arthrogryposis (Freeman-Sheldon Syndrome) is a rare disorder involving muscles which has also been called Whistling Face Syndrome.  The disorder usually involves at least two or more body areas with contractures of the hands and feet being common.

Distal Arthrogryposis may be sporadic or can be inherited in an autosomal dominant (50%) and autosomal recessive manner (25% if both parents are gene carriers).

One of the characteristics of autosomal dominant disorders which is due to the inheritance of one deleterious mutation in a gene is variable penetrance and variable expression. This means that the disease can be very variable from very mild (which might even suggest that the deleterious gene is not present) to more severe than the parent’s condition.

Other manifestations of Distal Arthrogryposis can include:

  • Craniofacial abnormalities
  • Spinal abnormalities
  • Small mouth
  • Pursed lips
  • Prominent cheeks
  • “Whistling” facial appearance
  • Small jaw
  • Flattened midface
  • High arched palate
  • Small tongue

Mutations in the MYH3 gene on chromosome 17p13.1 may be identified in up to 99% of individuals with Distal Arthrogryposis.

It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Distal Arthrogryposis) and the family wants to know from the healthcare provider: 

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

Resources:http://www.faces-cranio.org/Disord/Freeman.htm 

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