ACMG Guidelines Flashcards
Early Onset Alzheimers Disease (EOAD)
Onset of symptoms prior to 65 years
Offer genetic testing for APP, PSEN1, PSEN2 with adequate counseling, a full neuro-phsycological and neurological evaluation
Inheritance
-Autosomal dominant: 3+ individuals in 2+ generations affected. 2 individuals must be 1st degree relatives of the third. Offer genetic testing.
Familial: More than one individual is affected and 2+ affected individuals are at least 3rd degree relatives
How does having an affected 1st degree relative affect risk?
It doubles
Risk to develop Alzheimer’s disease
10-12%
Advanced paternal age defined as _________
40 and older
Recommendations for prenatal counseling session for father of babe with advanced paternal age
The pregnancy should be treated as any other but include a discussion about a potentially increased risk of Down Syndrome attributable to increased paternal age. An ultrasound is recommended at 18-20 weeks to evaluate fetal growth and development (however, it is unlikely to detect many of the conditions of interest).
Are there currently screening or diagnostic test panels to specifically target conditions increasing with paternal age?
No
Advanced Paternal Age is associated with an increased risk for complex disorders such as: (4 answers)For most conditions, the relative risk is two or less though
NAME?
The mutation rate is higher in men than women, and increases with paternal age because _________________________________
Because of the large number of cell divisions during spermatogenesis
The conditions most strongly associated with advanced paternal age are those caused by mutations in the form of single base substitutions (autosomal dominant) and include what? (7 conditions)
- Achondroplasia
- Pfeiffer Syndrome: Premature fusion of certain skull bones (craniosynostosis). Also affects bones in the hands and feet. More than half of all children with Pfieffer syndrome have hearing loss; dental problems are also common. (Genes:
ONTD’s
Screening methods include:
- Ultrasound- Done between 18 and 20 weeks. Detection rate is dependent on the institution.
- MSAFP- Done between 15 and 20 weeks. Optimal time: 16-18 weeks. Detects 75-90% of all ONTD’s, 95+% of anencephaly and 85% of ventral wall defects.
Diagnostic test:
- Amniocentesis: Amniotic fluid AFP and Acetylcholinesterase
Factors that affect maternal serum screening results
- Appropriate dating
- twin v. singleton (presence of twins increases cut-off’s 2x)
- Race
- IDDM (diabetes)
- Family history
- Maternal weight
Diagnostic tests for fetal aneuploidy
Detection rate is virtually 100% (dates based on ACMG guidelines, not Magee or West Penn’s protocol)
- CVS- can be done between 10w and 13w
- Amniocentesis- can be done at 15 weeks
What is the time cut-off for a discrepancy in gestational age after an U/S that a test result needs to be reinterpreted?
>10 days
What does first trimester screening measure?
- Pregnancy-associated plasma protein A (PAPP-A)
- Human chorionic gonadotropin (hCG)
- Nuchal translucency (NT) measurement
When is blood drawn for first trimester screening?
Between 9 weeks and 13 weeks 6 days gestation
(Crown rump length 24 - 84 mm)
What chromosome conditions does first trimester screening look for?
- Down Syndrome
- Trisomy 18
What first trimester screening markers are indicative of trisomy 21?
- High hCG
- Low PAPP-A
What first trimester screening markers are indicative of trisomy 18?
Low hCG
Low PAPP-A
What is the nuchal translucency (NT)?
NAME?
What are increased NT measurements associated with?
NAME?
ACOG recommends that patients with a fetal NT measurement of 3.5 mm or higher should be offered what?
NAME?
Second Trimester Screening (when is it performed and what does it screen for) - also referred to as “quad screen”
- Performed at 15 - 20 weeks
- Screens for trisomies 21 and 18 as well as open neural tube defects (ONTDs)
What are the biochemical markers that second trimester screening uses
AFP
hCG
uE3
Inhibin A
What is the cutoff risk for Down Syndrome for second trimester screening?
1 in 270
Detection rates of second trimester screening for Down Syndrome
- Detects ~75% of the cases of Down Syndrome cases for women under 35
- 80% of the cases of Down Syndrome in women 35+
What is indicative of Down Syndrome in second trimester screening?
High hCG and inhibin
Low uE3 and AFP
What is the “triple test”
- Part of second trimester screening- AFP, hCG, and uE3 are considered the “triple test”
- Has a sensitivity of ~65% for Down Syndrome and 70% for trisomy 18
What is indicative of trisomy 18 in second trimester screening?
Low hcg, uE3, and AFP
ACMG recommends that all women should have the option of ___________
- Invasive diagnostic testing for fetal aneuploidy by CVS or amniocentesis
- Screening for aneuploidy and ONTD’s for those that present for prenatal care before 20 weeks gestation
Women who undergo first trimester screening and/or CVS should be offered __________
MSAFP screening and/or an ultrasound for the detection of neural tube defects between 15 and 20 weeks gestation
True or False: Fragile X syndrome is the most common cause of inherited mental retardation
TRUE
Mutation that causes Fragile X:
FMR1 gene on the X chromosome
Symptoms of Fragile X Syndrome
Large ears
Large testicles
ID
Austism
98% of the cases of fragile X syndrome are caused by what mutation
An expansion of an unstable CGG repeat sequence located in the 5’ untranslated region (UTR) of the FMR1 geneThe full mutation form of FMR1 gene consists of over 200 repeats and is abnormally hypermethylated
What is responsible for the intellectual disability?
The lack of the gene product, FMRP (an RNA-binding protein)
Prevalence of Fragile X
1/4000 males have fragile X syndrome
A pre-mutation of Fragile X is associated with:
Pre-mutation (most often clinically reported as 55+ repeats) is most strongly associated with premature ovarian failure (POF) which is clinically defined as the cessation of menses before the age of 40.
Among women who carry the premutation, approximately 21% have POF compared to only 1% in the general population.
What late-onset neurodegenerative disorder has recently been associated with the premutation?
Late onset neurodegenerative disorder with tremor/ataxia syndrome (FXTAS) has been identified in men who carry the premutation and a small proportion of women with the premutation.
Clinical symptoms: cerebellar ataxia and intention tremor
Penetrance: in men 50+: ~20-40% but more research is needed to accurately define risks of age-related penetrance
Testing Techniques for Fragile X
PCR for CGG expansion in FMR1
Southern blot for GCC expansion
When should Fragile X testing be considered?
NAME?
Approaches to Fragile X Testing
- DNA analysis if one is testing specifically for fragile X
- For isolated cognitive impairment, DNA analysis for fragile X should be performed as part of a comprehensive genetic evaluation
Intellectual Disability is defined as
A congenital limitation in intellectual functioning and adaptive behavior
Intellectual Disability levels:- Mild- Moderate- Severe
Mild: IQ of 50 - 70
Moderate: IQ of 35 - 50
Severe: IQ of 20 - 35
Global developmental delay (DD) is defined as:
Significant delay in two or more of the following areas: cognition, speech/language, gross/fine motor skills, social/personal skills, and daily living
DD is evidenced as age-specific deficits in learning skills and adaptation in comparison with chronological peers
The term of DD is generally reserved for children
What is the most common cause of MR/DD
Chromosome abnormalities
What diseases should Ashkenazi Jewish people be screened for in a prenatal setting?
- Familial Dysautonomia
- Fanconi Anemia group c
- Tay Sachs
- Canavan Disease
- Neimann Pick type A
- Bloom Syndrome
- Mucolipidosis IV
- Gaucher Disease type 1
Carrier frequency for Cystic Fibrosis in the Caucasian population
1 in 25
Who should be screened for sickle cell?
African American population.
1 in 10 are carriers for S trait.
The disease encompasses a group of disorders characterized by the inheritance of at least one hemoglobin S trait.
HbSS- sickle cell anemia, caused by 2 copies of the s trait
HbSC- Also known as beta thalassemia, caused by compound heterozygous inheritance of both hemoglobin s trait and hemoglobin c trait.
Hemoglobin electrophoresis or genetic testing can diagnose these individuals.
Beta Thalassemia
Common in Mediterranean and middle eastern populations, carrier frequency is difficult to establish.
- Beta +: reduced beta-globin production
- Beta 0: absence of beta-globin production
Alpha Thalassemia
Only HbBart and HbH are clinically significant.
HbBart: deletion/dysfunction of all 4 alpha globin alleles, no residual function
HbH: Deletion/dysfunction of 3 alpha globin alleles, little residual function
Carriers of the alpha thalassemia trait can be:
Alpha 0-: Deletion/dysfunction of 2 alpha globin alleles, often in cis (–/++)
Alpha +: deletion/dysfunction of 1 alpha globin allele
Peripheral blood smear or hemoglobin studies can be performed for identification of carriers or affected individuals in addition to genetic studies.
Steps for carrier screening
Preconception: the mother should be screened first, screening should be based on her ethnicity. counsyl offers panels which cover a large majority of autosomal recessive diseases. Father should be tested after mothers results are received, if she is a carrier he can be screened for those particular diseases/mutations.
Prenatal screening works the same way.
Spinal Muscular Atrophy (SMA)
Severe neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, which results in proximal muscle weakness and paralysis
What is the second most common fatal autosomal recessive condition after cystic fibrosis?
Spinal Muscular Atrophy (SMA); prevalence 1 in 10,000 live births and a carrier frequency of 1/40 - 1/60
Spinal Muscular Atrophy (SMA) type 1 (Werdnig-Hoffman)
characterized by severe, generalized muscle weakness and hypotonia at birth or within the first 3 months of life. Death from respiratory failure usually occurs within the first 2 years.
SMA type II
Children are able to sit, although they cannot stand or walk unaided and survive beyond 4 years.
Type III SMA (Kugelberg-Welander)
Milder form, with onset during infancy or youth: patients learn to walk unaided
Primary SMA determining gene
- Survival Motor Neuron gene (SMN)
- SMN1: on 5q13 exon 7 (homozygously absent in approximately 95% of affected patients, with few exceptions)
- SMN2: 5q13.2 ( can help replace some of the missing SMN protein. In people with spinal muscular atrophy, having multiple copies of the SMN2 gene is usually associated with less severe features of the condition that develop later in life)
Limitations of a SMA carrier test
- Approximately 2% of SMA cases arise as the result of de novo mutation events (high compared to most autosomal recessive disease)
- The copy number of SMN1 can vary on a chromosome; we have observed that approximately 5% of the normal population possess t
Who is being offered SMA carrier testing?
Individuals with a family history. However, ACMG recommends that since SMA is present in all populations, carrier testing should be offered to all couples.
What chromosomes does NIPT look at?
Chromosomes 21, 18, 13, X and Y
What should always be offered if NIPT results come back as positive?
Amniocentesis or CVS
What chromosomal abnormalities would not be detected?
Translocations,
What should also be offered as an alternative when fetal anomalies are detected?
Ultrasound, amnio, CVS
Is NIPT able to distinguish the specific types of Down Syndrome?
No, it cannot determine if Down syndrome is due to the presence of an extra chromosome, a Robertsonian translocation, or high-level mosaicism
When is NIPT offered?
- After 10 weeks gestation
- Usually offered between 10 and 20 weeks gestation, which allows time for follow-up of positive test results
- Reasonable to offer NIPT after 20 weeks if an expectant mother desires information regarding risk, reassurance, or kno
NIPT does not screen for open neural tube defects, what still should be offered at 15 - 20 weeks?
MSAFP, to screen for open neural tube defects
What should pretest counseling include?
- A brief explanation of the purpose of NIPT
- Advantages of NIPT compared with maternal serum screening (higher detection rates, lower false-positive rates)
- Considerations for follow-up invasive testing if NIPT is positive
- Limitations of NIPT
Recurrence risk for autism when one sibling is affected
3-10%
What type of tests should be ordered when a child has autism or an autism spectrum disorder?
microarray, chromosomes and fragile X testing (carrier testing in mom if prenatal)
skeletal dysplasias
A group of more than 350 disorders of the skeleton, can be broken down into two relatively distinct groups. The more we learn the more blurred this distinction becomes.
Osteochondroplasias/skeletal dysplasia: disorders with generalized abnormalities of the skeleton
Dystoses: disorders that have a singe or group of abnormal bones
Inheritance
AD, AR, x-linked, imprinting errors, somatic mosaicism or teratogen caused.
Homozygosity or compound heterozygosity can cause what sort of complication
Lethality in many cases results from the inheritance of two mutations that cause skeletal dysplasias. This is usually, though not always, due to pulmonary insufficiency resulting from small chest circumference or concomitant visceral abnormalities.
Ultrasound in prenatal diagnosis
long bones
What is Factor V Leiden
A clotting factor that causes venous thrombosis. It can cause complications in pregnancy and MI in young females who smoke.
Who should be tested?
- anyone younger than 50 with an venous thrombosis
- Venous thrombosis at unusual sites; hepatic, mesenteric, cerebral)
- Recurrent venous thrombosis
- Venus thrombosis and a strong family hx of thrombotic disease
- Venous thrombosis during pregnancy or while taki
Testing methods
Patients who test positive through functional assays should have DNA studies ordered to assess heterozygous or homozygous status. Heparin therapy and lupus can confound test and these patients should proceed to genetic testing.
Risk factors and screening
it is not recommended that engagement in a risk factor be an indication for genetic testing.
Risks associated with a mutation
Risk for venous thrombosis is increased 7x in heterozygous carriers. There is a 20x increased risk in homozygous mutation carriers.
What is OI?
A condition in which individuals have bones that break easily, often from mild trauma or with no apparent cause
Other symptoms of OI
Triangular shaped face
scoliosis
Easy bruising
Hearing loss
Bowel obstruction
MVP
Delayed gross motor development
Inheritance pattern in OI
Austosomal dominant
Genes responsible for ~90% of OI cases
COL1A1
COL1A2
OI Type II
Lethal perinatal type (can detect on U/S at 14 weeks +)
Type of OI that is Autosomal Recessive
OI type VII
Laboratory testing for OI
- For pregnancies at risk for most forms of OI on basis of family history:
- Biochemical analysis of type I collagen from cultured CVS cells can be offered if collage screening studies have been completed on the affected parent or previous affected infant
Types of hearing loss
NAME?
Prevalence
2 - 3 out of every 1,000 children born in the U.S. are deaf or have hearing loss significant enough to effect speech and language development
(True or False) Newborn hearing screening is mandated throughout the U.S.
TRUE
95% of newborns with hearing loss identified by newborn hearing screening programs are born to ___________ parents
hearing
How are the majority of genetic hearing loss inherited?
Autosomal recessive pattern; The gene, GJB2, accounts for the larget proportion of autosomal recessive early childhood hearing loss
What factors are used to describe hearing loss?
- Age of onset (congenital, prelingual, postlingual, adult-onset, or presbycusis [age-related late-onset]
- Type of hearing loss
- laterality and symmetry of the hearing loss
- Stability of the hearing loss
- Degree of hearing loss
- Configuration of the hearing loss
What should first be done in a clinical evaluation to diagnose the etiology of hearing loss?
CMV testing, imaging, or other testing based on suspected etiology (e.g., rubella, meningitis)
Patient-focused medical and birth histories and a three generation pedigree and family medical history obtained, and a physical examination that focuses on dysmorphic physical findings
What genetic testing can be performed for syndromic hearing loss?
Single-gene tests, hearing loss sequencing panels, WES, WGS, chromosome analysis, or microarray-based copy-number analysis, depending on clinical findings
What genetic testing can be performed for suspected nonsyndromic hearing loss?
Single-gene tests such as GJB2 and GJB6, gene panel tests, or NGS testing based on history and findings
What other testing should be performed to evaluate the etiologic diagnosis of hearing loss?
- Congenital Cytomegalovirus Infection (CMV) is a common cause of pediatric hearing loss, and testing by rapid culture or PCR of saliva or urine samples from newborns are recommended
- CMV testing is most diagnostic ~6 weeks of age because the likelihood that older children may have been exposed to CMV after birth
Psychosocial challenges with genetic counseling and deafness
Unity of Deaf community, deaf parents may want deaf child
Terminology to use in sessions with deaf or hard-of-hearing patients
- Neutral or balanced terminology:
- “chance” instead of “risk”
- “deaf” or “hearing” instead of “affected” or “unaffected”
- do NOT use the words “handicapped,” “pathology,” or “impairment”
- DO NOT TREAT DEAFNESS OR HEARING LOSS AS A BAD THING
Genetic testing method most commonly used for deafness today
Next-gen sequencing
What is hemihyperplasia?
congenital asymmetrical overgrowth associated with embryonic tumors including Wilm’s tumor and hepatoblastoma.
Patients should have abdominal ultrasounds until the age of 7 and AFP levels measured until the age of 4 to monitor possible growth of abdominal tumors, these screenings should be performed every 3 months.
What is a similar genetic disorder to isolated hemihyperplasia?
Beckwith-Weideman Syndrome
How can you differentiate between BWS and Isolated Hemihyperplasia?
There is no identified single gene for IH, therefore molecular studies are unhelpful. Tumor studies should be done in patients at risk.
Occaisionally patients are found to have a mutation, this is not the majority of IH patients.
70% of patients with BWS will have an epigenetic or genetic finding.
Other overgrowth syndromes
NF1, BWS, Mosaic trisomy 8, proteus syndrome, plus disorders associated with vascular malformations
Possible genetic findings in isolated hemihyperplasia
Loss of maternal methylation, UPD and hypermethylation
Tumors and isolated hemihyperplasia
Incidence is roughly 6%.
Many of these tumors are embryonal with the vast majority of them identified as Wilm’s tumors, hepatoblastomas, and adrenal cell carcinomas.
The majority are seen in the abdomen, though they can be seen in other parts of the body.
What is Wilm’s tumor?
A malignant tumor of the kidney, of a type that occurs in young children.
What is the overall carrier rate of “Jewish Genetic Disorders” in the AJ population?
1 /4 to 1 /5 Ashkenazi Jews are carriers for one of these disorders
Importance of the history of Tay-Sachs and the carrier screening program
Over 30 years ago, the development of an accurate and reliable biochemical test led to a successful carrier screening program for Tay-Sachs.
The subsequent widespread adoption of Tay-Sachs carrier screening RESULTED IN A SIGNIFICANT DROP IN THIS DISEASE among the AJ population
What diseases should be included when offering carriers screening to couples of AJ descent when pregnant or considering pregnancy?
- CF- Canavan disease
- Familial dysautonomia
- Tay-Sachs
- Fanconi Anemia group C
- Niemann-Pick type A
- Bloom Syndrome
- Mucolipidosis IV
- Gaucher disease Type 1
(carrier screening for these disorders should include testing for specific mutations)
How is it determined what diseases to add to the recommended list for carrier screening?
- Natural history of disorder should be well understood and carry a potential for significant morbidity and/or mortality in the homozygous or compound heterozygous state
- Based on available literature there should be either >90% detection rate or an allel
What should occur in the counseling of this carrier screening?
If only one partner in a couple is of AJ descent should testing be offered?
Yes, ideally the Jewish member of the couple should be tested first, and if positive, the other partner should be tested for that gene regardless of background
Carney Complex
- Gene: PRKAR1A
- Characterized by: pale brown to black lentigenes; myxomas of the heart, skin, and breast; primary pigmented nodular adrenocortical disease; large cell calcifying Sertoli cell tumors
- Psammomatous melanotic schwannoma (a rare nerve sheath tumor) can also occur
- 50%+ of patients with isolated primary pigmented nodular adrenocortical disease have a PRKAR1A mutation
- REFERRAL: Personal hx or 1st-degree relative with i)primary pigmented nodular adrenocortical disease or ii) two or more diagnostic criteria
Birt-Hogg-Dube Syndrome (BHD)
- Gene: FLCN
- Characterized by the presence of classic skin lesions (fibrofolliculomas, perifollicular fibromas, trichodiscomas, or angiofibromas, and acrochordons); bilateral and multifocal renal tumors (chromophobe clear cell renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, occasionally clear cell renal carcinoma); multiple bilateral lung cysts often associated with spontaneous pneumothorax
- REFERRAL: individual with a personal or 1st-degree relative history of i) 5 or more BHD associated facial or truncal papules, ii) early onset (
Constitutional mismatch repair deficiency
- Recessive condition caused by biallelic mutations in the MMR genes
- Characterized by a high risk of developing cancers during childhood, including LS-associated cancers, hematologic malignancies, and embryonic tumors- Individuals affected with this have NF-1 type features with cafe-au-lait macules and skinfold freckling. Lisch nodules, neurofibromas, and tibial pseudoarthosis in occasional cases.
- Individuals with this do not always have a fam. hx of cancer
- REFERRAL: any individual with a personal hx or a 1st-degree relative with i) LS-associated cancer in childhood, ii)another type of childhood cancer AND one or more of the following features: i) cafe-au-lait macules, skinfold freckling, Lisch nodules, neurofibromas, tibial pseudoarthrosis, or hypopigmented skin lesions; ii) fam hx of LS-associated cancer; iii) a second primary cancer; iv) a sibling with a child hood cancer; or v) consanguineous parents
Cowden Syndrome
- Gene: PTEN
- Characterized by benign skin findings, macrocephaly, increased risk for breast (30 - 85%; often early-onset), follicular thyroid (10 - 38%), renal cell (34%), endometrial (5 - 28%), and CRC (9%), possibly melanoma (6%)
- REFERRAL: Any individual with a personal hx or first degree relative with i) Lhermitte-Duclose disease dx after 18; ii) any three criteria from the major or minor diagnostic criteria list in the same person
Familial Adenomatous Polyposis (FAP) and Attenuated FAP
- Gene: APC
- Characterized by: adenomatous colon polyps and increased lifetime risk for CRC (nearly 100% for FAP and 70% for AFAP)
- FAP = 100+ colon polyps; at increased risk for duodenal (4 - 12%), pancreatic (~2%), and papillary thyroid (cribriform morular variant) cancers as well as hepatoblastoma by age 5 and medullolastoma
- AFAP: 30 - 100 colon polyps- REFERRAL: any individual with personal or 1st-degree relative with i) 10+ adenomatous colon polyps with or without a CRC or other FAP-associated cancer; ii) a cribriform morular variant of papillary thyroid cancer; iii) a desmoid tumor; or iv) hepatoblastoma dx before age 5
Familial Gastrointestinal Stromal Tumor (GIST)
Genes: KIT, PDGFRA, SDHB, SDHC- Individuals with germline mutations in KIT can have hyperpigmentations, mast cell tumors, or dysphagia
- PDGFRA mutations have been associated with large hands- Individuals with NF1 can also develop GISTs
- Wild type GISTs are defined as GISTs that do not have detectable mutations in KIT, PDGFRA, or BRAF
- No published guidelines for referral; recommendations based on expert opinion
- REFERRAL: should be considered for any individual with a personal hx or 1st-degree relative with i)3+ close relatives with GIST; ii)wild-type GIST; or iii) individuals with 3+ GISTs
Familial Pancreatic Cancer
- Most common cause of familial pancreatic cancer: BRCA2 mutations, other genes include CDKN2A, PALB2, or ATM
- REFERRAL: any individual with a personal hx or 1st-degree relative with i) AJ ancestry and pancreatic cancer at any age; ii) pancreatic cancer and a close relative with pancreatic cancer; iii) 3+ cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer; iv) 3+ cases of pancreatic cancer and/or melanoma
Familial Prostate Cancer
- Autosomal dominant, recessive, and X-linked patterns of inheritance have been demonstrated in families with multiple cases of prostate cancer
- REFERRAL: should be considered for any individiaul with a personal history of or 1st-degree relative with i) 3 or more first-degree relative with prostate cancer; ii) 2 or more cases of prostate cancer dx before 55; or iii) aggressive prostate cancer (Gleason score 7+) and 2+ cases of breast, ovarian, or pancreatic cancer
HBOC
- Genes: BRCA1 and BRCA2
- Characterized by increased risks for early-onset breast, multiple breast primaries, male breast, and epithelial ovarian, fallopian tube, or primary peritoneal cancers, as well as pancreatic, prostate, and melanoma
- Triple negative breast cancer has been strongly associated with BRCA1 mutations
- REFERRAL: use NCCN guidelines for this
Hereditary diffuse gastric cancer
- Gene: CDH1
- Increased risk for diffuse gastric cancer, lobular breast cancer, and signet ring CRC
- CDH1 mutations occur in 25-50% of individuals who mee criteria
- REFERRAL: any individual with a personal history of or 1st-degree relative with i) diffuse gastric cancer dx
Hereditary leiomyomatosis and renal cell cancer
- Gene: FH gene
- Characterized by increased risks for renal cancer and cutaneous and uterine leiomyomas
- REFERRAL: Individuals with cutaneous leiomyoma and renal cell tumors of one of three types (papillary type 2, collecting duct, and tubulopapillary)
- REFERRAL should also be considered for any individual with a personal hx or first-degree relative with i) cutaneous leiomyomas or ii) RCC with histology characteristic of hereditary leiomyomatosis and renal cell cancer
Hereditary Melanoma, also known as familial atypical mole and malignant melanoma
- Genes: CDKN2A/ARF gene
- Characterized by multiple melanocytic nevi (usually >50) and family hx of melanoma
- Individuals with hereditary melanoma have a 17% risk for pancreatic cancer by age 75
- REFERRAL: should be considered for any individual with a personal hx or 1st-degree relative with i) 3 or more melanomas in the same person or ii) three or more cases of melanoma and/or pancreatic cancer
Hereditary mixed polyposis syndrome
- Gene: The major gene(s) responsible have not been identified; however some cases are caused by mutations in BMPR1A and a founder mutation involving the GREM1 gene was identified in AJ patients
- Characterized by multiple polyps of mixed histology (hyperplastic, adenomatous, and juvenile polyps) leading to an increased risk for CRC
- Referral should be considered for any individual with a personal hx of or 1st-degree relative with 10+ colorectal polyps with mixed histology
Hereditary Papillary RCC
- Gene: MET
- Characterized by an increased risk of developing papillary type 1 RCC
- REFERRAL: should be considered for any individual with a personal hx or 1st-degree relative with a papillary type 1 RCC
Hereditary paraganglioma-pheochromocytoma syndrome
- Genes: SDHB, SDHD, SDHC, SDHAF2, MAX, TMEM127
- Characterized by an increased risk for paragangliomas and pheochromocytomas
- REFERRAL: should be considered for any individual with a personal history of or a first-degree relative with a paraganglioma or pheochromocytoma
Hereditary Retinoblastoma
- Gene: RB1- Characterized by a malignant tumor of the retina, usually occurring before age 5
- Estimated ~40% of all retinoblastomas are hereditary
- REFERRAL: any individual with a personal hx or a first-degree relative with a retinoblastoma
Juvenile Polyposis Syndrome
- Genes: SMAD4 and BMPR1A
- Characterized by juvenile-type hamartomatous polyps throughout the GI tract
- The term “juvenile polyp” refers to a specific histologic type of polyp, not the age of dx
- The risk for GI cancers (mainly CRC, though stomach, upper GI tract, and pancreas have been reported) range from 9 to 50%
- Extraintestinal features such as valvular heart disease (11%), telangiectasia or vascular anomalies (9%, all in SMAD4 carriers), and macrocephaly (11%) can occur- Some individuals with JPS due to mutations in SMAD4 may also have symptoms of hereditary hemorrhagic telangiectasia
- REFERRAL: should be considered for any individual with a personal hx or of 1st-degree relative with i) 3-5 cummulative histologically provin juvenile GI polyps; ii) any number of juvenile GI polyps with a positive fam hx of JPS; or iii) multiple juvenile polyps located throughout the GI tract
Li-Fraumeni
- Gene: TP53
- Characterized by the core cancers of breast, brain, adrenocortex, and non-Ewing sarcoma with onset often before 50 and multiple primary tumors.
- Young age of dx (
Lynch Syndrome
- MMR genes (MLH1, MSH2 [including methylation due to an EPCAM deletion], MSH6, PMS2)
- Characterized by CRC (risk 40 - 80%) and endometrial cancer (25 - 60%), ovarian (4 - 24%), and gastric (1 - 13%) cancers
- Tumors associated with Lynch Syndrome: Colorectal adenocarcinoma, endometrial adenocarcinoma, urothelial carcinoma, gastric cancer, ovarian cancer, small bowel cancer, glioblastoma, sebaceous adenocarcinoma, biliary tract cancer, pancreatic cancer
- REFERRAL: any individual with a personal hx or first-degree relative with
i) colorectal or endometrial cancer dx before age 50;
ii) colorectal or endometrial cancer dx at or after age 50 if there is a 1st-degree relative with CRC or endometrial cancer at any age;
iii) synchronous or metachronous CRC or endometrial cancer;
iv) sebaceous adenoma or carcinoma and one or more additional case of any LS-associated cancer in the same person or relatives;
v) a tumor exhibiting MMR deficiency;
vi) fam hx of 3+ LS-associated cancers
Melanoma-Astrocytoma syndrome
- Genes: CDKN2A and p14ARF, p14ARF alone, and possibly the ANRIL antisense noncoding RNA
- Leads to an increased risk for melanoma and astrocytoma tumors
- REFERRAL: should be considered for any individual with a personal hx or first-degree relative with i) melanoma and astrocytoma in the same person or ii) one case of melanoma and one case of astrocytoma in 2 first-degree relatives
Multiple Endocrine Neoplasia type I (MEN1)
- Gene: MEN1
- Characterized by increased risk of endocrine and nonendocrine tumors
- No single MEN1-associated tumor is sufficient to warrant GC referral, with the exception of gastrinoma
- REFERRAL: any individual with a personal hx or first-degree relative with
i) 2+ different MEN1-associated tumors (adrenal, parathyroid, pituitary, pancreas, or thymic tumor or bronchial carcinoid tumor) in the same person;
ii) gastrinoma;
iii) multiple different pancreatic neuroendocrine tumors in the same person;
iv) parathyroid adenoma dx before 30;
v) parathyroid adenomas involving multiple glands; or
vi) parathyroid adenoma with fam hx of hyperparathyroidism or MEN1-associated tumors
Multiple Endocrine Neoplasia type II (MEN2)
- Gene: RET
- Characterized by increased risks for medullary thyroid cancer [MTC] (~100%), pheochromocytomas (50% or lower), and parathyroid disease (30% or lower)
- As many as 25% of individuals with MTC have a RET mutation
- REFERRAL: any individual with a personal history of or first-degree relative with i) MTC; ii) pheochromocytomas; iii) oral or ocular neuromas (lips, tongue, sclera, or eyelids); iv) diffuse ganglioneuromatosis of the GI tract
MUTYH-associated polyposis (MAP)
- Gene: MUTYH
- Autosomal recessive
- Characterized by an increased risk for adenomatous colon polyps and colorectal cancer (80%)
- REFERRAL: any individual with a personal history of or a first-degree relative with i) 10+ cumulative adenomatous colon polyps with or without CRC or ii)MMR proficient CRC diagnosed
Nevoid basal cell carcinoma syndrome
- Gene: PTCH
- Characterized by the presence of multiple jaw keratocysts beginning in the teens and multiple basal-cell carcinomas beginning in the 20’s
- Physical features such as macrocephaly, bossing of the forehead, coarse facial features, facial milia, and skeletal anomalies are present in most individuals
- Less common features include cardiac fibromas (2%), ovarian fibromas (20%), medulloblastoma (primitive neuroectodermal tumor; 5%)
- Dx made clinically when an individual has 2 major dx criteria and 3 minor dx criteria
- REFERRAL: should be considered for any individual with a personal hx of or 1st-degree relative with any two criteria
Peutz-Jeghers Syndrome (PJS)
- Gene: STK11
- Characterized by mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genetalia, or fingers; multiple hamartomatous polyps in the GI tract; and increased risks for colorectal, pancreatic, gastric, and small intestinal cancers. Also increased risks for breast cancer, ovarian sex cord tumors with annular tubules, and adenoma malignum of the cervix and the testes, especially Sertoli cell tumors.
- REFERRAL: any individual with a personal hx of or first-degree relative with
i) 2+ histologically confirmed PJ GI polyps;
ii) one or more PJ GI polyp and mucocutanous hyperpigmentation;
iii) ovarian sex cord tumor with annular tubules;
iv) adenoma malignum of the cervix;
v) Sertoli cell tumor;
vi) pancreatic cancer and one or more PJ GI polyp;
vii) breast cancer and one or more PJ GI polyp; or
viii) one or more PJ polyp and a positvie family history of PJS
Rhabdoid tumor predisposition syndrome types I and II
- Gene: SMARCB1 (type 1); SMARCB4 (type 2)
- Characterized by an increased risk for rhabdoid tumors (rare and aggressive tumors in children).
- REFERRAL: any individual with a personal history of or first-degree relative with a rhabdoid tumor, including small cell carcinoma of the ovary, hypercalcemic type.
Serrated Polyposis Syndrome (SPS)
- Unknown genetic cause; a genetics referral is indicated bc the diagnosis will affect future management and other polyposis syndromes should be ruled out
- Syndrome characterized by serrated polyps and an increased risk for CRC.
- REFERRAL: any individual with a personal hx of or 1st-degree relative with i) at least 5 serrated polyps proximal to the sigmoid colon, 2 of which are >1 cm in diameter, ii) >20 serrated polyps throughout the large bowel, or iii) any number of serrated polyps proximal to the sigmoid colon and a positive family hx of SPS
Tuberous Sclerosis Complex
- Genes: TSC1 and TSC2- Characterized by brain, kidney, and heart tumors, as well as skin and neurological abnormalities, among others.
- Skin lesions occur in ~100% of individuals, although none are pathognomonic
- REFERRAL: should be considered for any individual with a personal hx of or first-degree relative with any two criteria
Von Hippel-Lindau Syndrome (VHL)
- Gene: VHL
- Characterized by RCC (clear cell histology), hemangioblastomas, pheochomocytomas, and endolymphatic sac tumors.
- Simplex cases of CNS hemangioblastoma, pheochromocytoma, and endolymphatic sac tumor are sufficient to warrant genetic counseling referral
- REFERRAL: should be considered for any individual with a personal hx of or 1st-degree relative with i) clear cell RCC if he or she (a) has bilateral or multifocal tumors, (b) is diagnosed before age 50, or (c) has a close relative with clear cell RCC; ii) central nervous system hemangioblastoma; iii) pheochromocytoma; iv) endolymphatic sac tumor, or v) retinal capillary hemangioma
What is Pompe Disease? (also known as acid maltase deficiency [AMD] or glycogen storage disease type II [GSD11])
Disorder caused by a deficiency of the lysosomal enzyme acid-alpha-glucosidase (GAA)
Inheritance Pattern
Autosomal Recessive
Clinical presentation range in severity of Pompe disease
Ranges from a rapidly progressive infantile form which is uniformly lethal to a more slowly progressive late-onset form
Patients with infantile Pompe disease present in the first few months of life with _______________________
- hypertrophic cardiomyopathy
- generalized muscle weakness
- hypotonia- cardiomegaly
- respiratory distress
- failure to thrive
- followed by death from cardiorespiratory failure usually by 1 year
Late-onset Pompe disease is characterized by ________________________________
childhood, juvenile, or muscular variant that is a heterogeneous group usually presenting later than infancy and typically not including severe cardiomyopathy.
adult-onset form characterized by a slowly progressive myopathy predominantly involving skeletal muscle that can present as late as the second to sixth decade of life
*Markedly reduced GAA activity
Diagnostic testing of Pompe disease
GAA activity in tissues such as cultured fibroblasts from skin biopsy, muscle biopsy, purified lymphocytes, mononuclear cells and lymphoid cell lines
Current gold standard of diagnostic testing of Pompe disease
- Measurement of GAA activity in skin fibroblasts (downside: can take up to 4 - 6 weeks)
Prenatal/preconception genetics
Personal history:
- Maternal age of 35+ for a singleton pregnancy
- Maternal age of 33+ for a twin pregnancy
- Consanguinity
- Abnormal FTS or STS with or w/o NT measure
- Teratogen exposure (CMV, radiation, medication, etc)
- fetal anomaly id’d through U/S or echo-Personal/family history of pregnancy complications (acute fatty liver of pregnancy)
- Carrier of an autosomal recessive condition-History of hydrops, still birth, 2+ pregnancy losses, or SIDS
- Progressive neurological condition with a known genetic etiology
- Statin induced myopathy
Personal (either member of the couple) or family history:
- spina bifida, cleft lip/palate or CHD
- known balanced translocation carrier, marker chromosome, or mosaic cell line carrier
- Hearing/vision loss
- Personal or family history of intellectual disability or developmental delay
Adult genetics
Personal history of:
- abnormal sexual maturation or delayed puberty
- tall or short stature-one or more birth defects
- six or more cafe-au-lait spots >1.5 cm in diameter
- statin induced myopathy
Personal or family history of:
- cancers (see NCCN guidelines)
- Cardiomyopathy, Long QT syndrome, hyperlipidemia
- suspected CTD
- Bleeding or clotting disorder
- progressive genetic neurological deterioration disorder
- vision loss such as retinitis pigmentosa, cataracts or macular degeneration
- early onset hearing loss-known genetic disorder
- mental illness
Close relative with sudden unexplained death at a young age
Pediatric referrals
need info
Potential diagnoses of short stature
Familial short stature, constitutional delay of growth, occult pulmonary, renal or gastrointestinal disease, endocrinopathies, and genetic disorders
Definition of short stature
height <3rd centile
One of the most common pathologic diagnoses of short stature is _________
chromosomal abnormalities, primarily Turner syndrome and its variants
If physical examination does not suggest a recognizable syndrome then ___________
then chromosome analysis should be performed, which has the added advantage of addressing the potential of mosaicism
If chromosome analysis is negative, what other genetic studies can be considered?
Molecular testing
