Tag Archives: #raregeneticdiseases

Split Hand Split Foot Malformations (SHFM)

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director 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.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their 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 was established in 1983 by Abbey Meyers and others.

Ectrodactyly, also referred to as Split Hand/Split Foot Malformations (SHFM) can be inherited in an autosomal dominant (50%), autosomal recessive (25% if both parents are gene carriers), sex (X) linked manner or can be part of several syndromes including some chromosomal abnormalities.

Several other organ systems as is seen in other ectodermal dysplasias involving:

  • Hair
  • Skin
  • Nails
  • Cleft lip or palate
  • Hearing abnormalities
  • Lacrimal or endocrine systems
  • Urinary systems
  • Developmental delay

Several families have been described where one or more generations appeared to have been “skipped” suggesting an autosomal dominant mode of inheritance with variable penetrance so that the condition was not “expressed” or was so minor as to not have been diagnosed.

At least 6 types of SHFM have been described:

  • 3 described as inherited in an autosomal dominant manner
    2 described as inherited as probably autosomal recessive
  • 1 as sex (X) linked

SHFM Types 1,4 and 5 described as probably autosomal dominant involve chromosome 7q21-q23, microdeletion chromosome 3q28 and a microdeletion of chromosome 2q31.1 respectively.

The two probable autosomal recessive SHFM types involve chromosomes 10q24-q25 [duplication](Type 3) and chromosome 12q11-q13 (Type 6). Type 2 SHFM involves the X chromosome at Xq26.

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. Ectrodactyly) 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.

Rare Genetic Diseases – Ectrodactyly

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, Life Sciences, 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. 

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their 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 was established in 1983 by Abbey Meyers and others.

Ectrodactyly, also referred to as Split Hand/Split Foot Malformations (SHFM) can be inherited in an autosomal dominant (50%), autosomal recessive (25% if both parents are gene carriers), sex (X) linked manner or can be part of several syndromes including some chromosomal abnormalities.

Several other organ systems as is seen in other ectodermal dysplasias involving:

  • Hair
  • Skin
  • Nails
  • Cleft lip or palate
  • Hearing abnormalities
  • Lacrimal or endocrine systems
  • Urinary systems
  • Developmental delay

Several families have been described where one or more generations appeared to have been “skipped” suggesting an autosomal dominant mode of inheritance with variable penetrance so that the condition was not “expressed” or was so minor as to not have been diagnosed.

At least 6 types of SHFM have been described:

  • 3 described as inherited in an autosomal dominant manner
    2 described as inherited as probably autosomal recessive
  • 1 as sex (X) linked

SHFM Types 1,4 and 5 described as probably autosomal dominant involve chromosome 7q21-q23, microdeletion chromosome 3q28 and a microdeletion of chromosome 2q31.1 respectively.

The two probable autosomal recessive SHFM types involve chromosomes 10q24-q25 [duplication](Type 3) and chromosome 12q11-q13 (Type 6). Type 2 SHFM involves the X chromosome at Xq26.

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. Ectrodactyly) 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. 

Ectrodactyly

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, Life Sciences, 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.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their 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 was established in 1983 by Abbey Meyers and others.

Ectrodactyly, also referred to as Split Hand/Split Foot Malformations (SHFM) can be inherited in an autosomal dominant (50%), autosomal recessive (25% if both parents are gene carriers), sex (X) linked manner or can be part of several syndromes including some chromosomal abnormalities.

Several other organ systems as is seen in other ectodermal dysplasias involving:

  • Hair
  • Skin
  • Nails
  • Cleft lip or palate
  • Hearing abnormalities
  • Lacrimal or endocrine systems
  • Urinary systems
  • Developmental delay

Several families have been described where one or more generations appeared to have been “skipped” suggesting an autosomal dominant mode of inheritance with variable penetrance so that the condition was not “expressed” or was so minor as to not have been diagnosed.

At least 6 types of SHFM have been described:

3 described as inherited in an autosomal dominant manner
2 described as inherited as probably autosomal recessive

1 as sex (X) linked.

SHFM Types 1,4 and 5 described as probably autosomal dominant involve chromosome 7q21-q23, microdeletion chromosome 3q28 and a microdeletion of chromosome 2q31.1 respectively.

The two probable autosomal recessive SHFM types involve chromosomes 10q24-q25 [duplication](Type 3) and chromosome 12q11-q13 (Type 6). Type 2 SHFM involves the X chromosome at Xq26.

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. Ectrodactyly) 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. 

Rare Genetic Diseases – MCAD

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director 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

MCAD) – Medium Chain ActylCoA Dehydrogenase Deficiency prevents converting fats to energy especially with fasting fatty acids → acetylCoA). MCAD is inherited in an autosomal recessive manner (25% if both parents are gene carriers).

MCAD is characterized by:

  • Vomiting
  • Lethargy
  • Seizures
  • Hypoglycemia

A mutation may be found in the ACADM gene.

Inheritance: 1 in 50,000

Diagnosis:

  •  Pregnancy – HELLP

Fatty Acid Oxidation Deficiency. Diagnosis: blood/urine (blood – acylcantiines (alanocylcarnitines)

Rx: Glucose – avoid starvation L carnitine?

Medicine: Ravicti

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.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their 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 was established in 1983 by Abbey Meyers and others.

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. Medium Chain AcylCoA Dehydrogenase Deficiency (MCAD)] 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.

MCAD

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director 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

MCAD) – Medium Chain ActylCoA Dehydrogenase Deficiency prevents converting fats to energy especially with fasting fatty acids → acetylCoA). MCAD is inherited in an autosomal recessive manner (25% if both parents are gene carriers)

MCAD is characterized by:

  • Vomiting
  • Lethargy
  • Seizures
  • Hypoglycemia

A mutation may be found in the ACADM gene.

Inheritance: 1 in 50,000

Diagnosis:

  •  Pregnancy – HELLP

Fatty Acid Oxidation Deficiency. Diagnosis: blood/urine (blood – acylcantiines (alanocylcarnitines)

Rx: Glucose – avoid starvation L carnitine?

Medicine: Ravicti

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.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their 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 was established in 1983 by Abbey Meyers and others.

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. Medium Chain AcylCoA Dehydrogenase Deficiency (MCAD)] 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. 

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