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Medical Genetics Flashcards

1
Q 
Neonatal hypoparathyroidism (with hypocalcemia)
Immunodeficiency
Congenital Heart Disease
A

DiGeorge Syndrome- 22q11.2 del

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2
Q

What are the etiologies (both environmental and genetic) associated with DiGeorge’s constellation of findings?

A 
Teratogens (maternal alcohol, maternal diabetes, maternal retinoic acid exposure)
chromosome abnormalities (10p deletion; 4q deletion; 22q11.2 deletion)
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3
Q

What considerations need to be made when ordering testing for 22q11.2 deletion syndrome?

A

Order MLPA and microarray
Most deletions are de novo (90%) so lack of fhx is not uncommon
There are several previous names for different combinations of symptoms

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4
Q

TBX1 gene

A

important developmental gene
traditionally lost in 22q11.2 A-B deletions and thought to be responsible for many associated features of the syndrome (e.g. conotruncal cardiac anomalies)

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5
Q

CRKL1 and SANP29

A

important developmental genes traditionally lost in 22q11.2 B-D/C-D deletions
individuals do still have typical associated features (even though they have in-tact TBX1 genes)
these kinds of deletions are frequently familial
Not picked up by traditional FiSH studies

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6
Q

Most common causes of congenital heart disease:

A
  1. Down syndrome

2. 22q11.2 del syndrome (but TOF is more often seen in this than in Down Syndrome)

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7
Q

Immunodeficiency/Autoimmune disease
Congenital heart disease
Palatal Defects
Hypocalcemia (resulting in seizures)/ Other endocrine abnormalities (e.g. thyroid disease, short stature, growth hormone deficiency, IUGR, etc.)
GU anomalies (renal agenesis, dysplastic kidneys, duplicated collecting system, hydronephorsis, inguinal hernia, cryptorchidism/hypospadias/absent uterus)
GI problems (esophageal dysmotility/severe feeding problems, intestinal malrotation, constipation, umbilical hernia, Hirschprung’s disease, esophageal atresia/TEF, imperforate anus)
Other birth defects (polydactyly, club foot, craniosynostosis)
Global Developmental Delay
Autism Spectrum Disorder
Psychiatric illnesses (Schizophrenia, depression, anxiety, OCD)

A

22q11.2 deletion syndrome (overall)

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8
Q

What psychosocial things should be considered when thinking about 22q11.2 del syndrome?

A

Diagnosis is often missed, especially in adolescents, adults, and non-caucasian individuals
Individuals can be diagnosed in adulthood by having a more severely affected child or via NIPS
Presentation is incredibly variable (even in identical twins)
Only about 10% of cases are inherited

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9
Q

What is the current NBS for 22q11.2 del syndrome?

A

Current trials are in the works, but NBS for SCID has picked up infants with 22q11.2 del syndrome due to low T-cells (67% of these patients have impaired T-cell production)

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10
Q

What signs of 22q11.2 del syndrome can be seen in pregnancy?

A

NIPS now uses microarray and can detect the deletions
Fetal Echos MAY (but not always) detect some of the associated cardiac anomalies (ductal dependent lesions are hard to detect)- important because early cardiac diagnosis is important for reducing morbidity
Polyhydramnios (can be a clue to a palatal abnormality)- sometimes the only prenatal clue
Prenatal US MAY detect some palatal issues (does NOT detect velopharyngeal dysfunction or submucosal cleft palate/bifid uvula)
IUGR
Rare prenatally (diaphragmatic hernia, polydactyly - pre and post axial -, club foot, radial ray defects, craniosynostosis)

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11
Q

What are the highlights of the guidelines for 22q11.2 del syndrome management?

A

treatment/monitoring of hypocalcemia/thyroid dysfunction (Ionized calcium, PTH, TSH; esp at times of bio stress like surgery and puberty and pregnancy - caution because can cause nephrocalcinosis)
PRN - infant stimulation and specialized educational interventions, ST, palatal eval/surgery, treatment of psych illnesses

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12
Q

What are pregnancy considerations for women with 22q11.2 Del syndrome?

A

risk for new onset hypocalcemia
adult congenital heart disease related risk
risks related to treatment for underlying idiopathic seizure disorders (potential teratogen exposures)
associated autoimmune disease
problems associated with underlying psyciatric disease
prenatal monitoring
future preconception counseling

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13
Q 
DDx for the following-
congenital heart disease
renal anomalies
ID
hearing loss
Immunodeficiency
A 
22q11.2 del
CHARGE/CHD7 mutation
Smith-Lemli-Opitz
Goldenhar
Alagille
Kabuki
Jacobsen (11qterdel)
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14
Q 
Congenital heart disease
Hemifacial microsomia/microtia/anotia
Conductive hearing loss
Butterfly vertebrae
Renal anomalies
A

Goldenhar

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15
Q

Congenital heart disease (TOF or peripheral pulmknary stenosis most common)
posterior embryotoxon
Butterfly vertebrae

A

Alagille

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16
Q 
Congenital heart disease (HLHS, ASD, PDA, VSD)
polydactyly
microcephaly with frontal narrowing, growth restriction
hypospadias
Y-shaped 2-3 toe syndactyly
renal anomalies
ID (often severe)
ptosis, abnormal ears, anteverted nares
low cholesterol
A

Smith-Lemli-Opitz
AR
DHCR7 gene (leads to deficiency of 7-dehydrocholesterol reductase)

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17
Q 
Congenital heart disease
Growth retardation
Hearing Loss
GU/renal anomalies
ID
Tortuous renal vessels
A

Jacobsen

11qterdel

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18
Q

What is the first line recommendations for children with global developmental delay / ID / ASD of unknown cause?

A 
Chromosomal microarray
Fragile X (FMR1) DNA analysis
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19
Q

Top 10 recurrent CNVs with found on CMA for DD/ID/ASD?

A

22q11. 2 del
16p11. 2 del
1q21. 1 del
15q13. 2-q13.3 del
22q11. 2 dup
7q11. 23 del
16p11. 2 dup
15q11. 2-q13 dup
15q11. 2-q13 del
1q21. 1 dup

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20
Q

Describe the inheritance of Fragile X Syndrome.

A

most common known inherited cause of ID/ASD
X-linked (Xq27.3) trinucleotide expansion disorder (CGG repeats in 5’ UTR) of the FMR1 gene
Maternal premutations can expand to full mutations in children
Paternal premutations passed to daughters typically have minimal expansion
AGG interruptions stabilize repeats (make less likely to expand)

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21
Q

What are the repeat levels for Fragile X syndrome?

A

Negative - <45
Intermediate - 45-54
Premutation (FXTAS/FXPOI) - 55-200
Full - >200

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22
Q

What is the mechanism for Fragile X syndrome (both premutation and full mutation)?

A

Premutation repeat carriers have undermethylation of the gene and produce more FMRP
Full repeat carriers are over-methylated and fail to produce FMRP (which is essential for neuronal functioning throughout life)

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23
Q

Mild to moderate ID, Autism Spectrum Disorder, Learning disabilities, psychiatric disorders
Long face, prominent ears
Poor eye contact, attention problems, shyness, and social anxiety

A

Females with FMR1 full mutations

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24
Q

Long face, prominent ears
Enlarged testicles
Variable degrees of ID
Autism spectrum disorder, autism symptoms, poor eye contact, hand flapping
Attention deficits, anxiety, speech difficulties

A

Fragile X syndrome

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25
Decreased ovarian reserve Infertility Early Menopause Onset around 30's
Fragile X- associated primary ovarian insufficiency (FXPOI)
26
``` Progressive gait ataxia Intention tremor Personality changes White matter lesions involving middle cerebellar penduncles (MCP) on MRI or other less specific findings (lesions of white matter or generalized atrophy) Parkinsonism Short term memory changes Executive function deficits Average onset around 60 y/o ```
Fragile X- associated Tremor Ataxia (FXTAS) 40-50% of premutation males >age50 have symptoms ~8-17% of premutation females develop symptoms late in adulthood
27
``` Broad thumbs and great toes (possibly with deviation) Postnatal growth deficiency prominent or beaked nose septum extending below alae nasi maxillary hypoplasia Hirsuitism Cardiac defects (PDA, VSD, ASD) Long eyelashes downslanting palpebral fissures ID (moderate) ```
``` Rubenstein-Taybi syndrome AD ~40% de novo CREBBP gene some microdeletions of 16p13.3 ```
28
``` malar hypoplasia (sometimes with zygomatic bone cleft) lower lid coloboma absent eyelashes medial to defect projection of scalp hair onto lateral cheek malformation of auricles or microtia external ear defects conductive HL micrognathia normal intelligence downslanting palpebral fissures ```
Treacher Collins Syndrome AD TCOF1 gene (less common in POLR1C and POLR1D)
29
``` prenatal growth deficiency microcephaly ID (mild to severe) hoarse voice bushy eyebrows synophrys long, curly eyelashes depressed nasal bridge anteverted nares thin upper lip hirsuitism cutis marmarota GI and GU anomalies syndactyly of 2nd-3rd toes micromelia (of upper and/or lower limbs) oligodactyly 5th finger clinodactyly flexion contracture of elbow ```
Cornelia de Lange Syndrome AD NIPBL gene (~60%) (some more rare AD/XL genes)
30
``` flat face with prominent eyes depressed nasal bridge high myopia cataracts retinal detachment hearing loss cleft palate (hard or soft or bifid uvula) *Pierre Robin sequence* joint hypermobility, early onset arthritis ```
Stickler syndrome AD COL2A1 (also associated with other conditions), COL11A1, COL11A2
31
``` postnatal growth deficiency (significant) long palpebral fissures eversion of lateral portion of lower eyelid arched eyebrows with sparse lateral third prominent, abnormal ears short nose heart defects (coarct, BAV, MVP, others) Cleft palate Sensorineural/conductive hearing loss Immunodeficiency Butterfly vertebrae fetal fingertip pads short 5th fingers joint hypermobility ID (usually moderate) ```
Kabuki syndrome AD MLL2 gene
32
What is the diagnostic criteria for NF1?
``` MUST have 2+ of the following: 6+ cafe-au-lait macules Inguinal or axillary freckling 2+ neurofibromas OR 1 plexiform neurofibroma Lisch nodules (2 or more) Optic glioma Tibial pseudoarthrosis OR sphenoid wing dysplasia 1st degree relative with NF1 ```
33
``` relative macrocephaly learning disability, mild ID, ADHD scoliosis CNS tumors malignant peripheral nerve sheath tumor cafe-au-lait macules inguinal/axillary freckling neurofibromas optic glioma lisch nodules tibial pseudoarthrosis sphenoid wing dysplasia ```
Neurofibromatosis type 1 AD NF1 gene
34
``` short stature heart defects (pulmonic valve stenosis, ASD, TOF) hypertrophic cardiomyopathy variable DD hypertelorism downslanting palpebral fissures thick eyelids ptosis posteriorly rotated ears with fleshy helices broad/webbed neck low posterior hairline pectus deformity, shield chest cryptorchidism bleeding diathesis ```
Noonan Syndrome AD PTPN11, SOS1, RAF1, KRAS, others
35
coloboma (unilateral or bilateral of iris, retina-choroid, or optic disc) heart defects (TOF, VSD, DORV, TA) choanal atresia (unilateral or bilateral choanal atresia or stenosis) restricted growth and development hypogonadotophic hypogonadism, cryptorchidism abnormal outer ears ossicular anomalies Immunodeficiency *Mondini defect of cochlea* hypoplastic semicircular ear canal with hearing loss Cranial nerve dysfunction (hyposomia or anosmia, facial palsy) facial celfts TE fistula square face broad, prominent forehead flat midface prominent nasal bridge and columella
CHARGE syndrome AD CHD7
36
*supraventricular aortic stenosis*, VSD, ASD, pulmonic valve stenosis vascular stenosis joint laxity/hypermobility, contractures, scoliosis, lordosis, short stature renal artery stenosis, aortic hypoplasia, other arterial anomalies visuospatial, cognitive differences medial eyebrow flare, preiorbital fullness, stellate iris, full lips, widely spaced teeth, dental caries hoarse voice premature grey hair hypercalcemia feeding difficulties emesis constipation DD outgoing, friendly personality
Williams syndrome 7q11.23 microdeletion encompassing the Elastin gene (ELN) - resulting in cardiac phenotype - and sometimes the LIMK1 gene - resulting in visuospatial and cognitive differences
37
*lissencephaly* ID, microcephaly, seizures, feeding difficulties, spasticity, hypotonia high forehead vertical ridging and furrowing of forehead small nose anteverted nostrils protuberant upper lip with thin vermillion border breathing difficulties almost no developmental milestones achieved death in early childhood
Miller-Dieker syndrome RARE 17p13.3 microdeletion (varies in size, loss of LIS1 seems critical for lissencephaly, involved in optimal neuronal migration)
38
severe neonatal hypotonia, growth restriction enlarged anterior fontanelle, tall forehead, flat face upslanted palpebral fissures hepatomegaly limb contractures, club feet epiphyseal stippling often fatal in 1st year of life, survivors have seizures, severe ID
Zellweger (cerebro-hepato-renal) syndrome | AR defect in preoxisomal biogenesis due to a PEX gene mutation (there are many PEX genes)
39
white hair, very pale skin, light colored irises
Type 1 oculocutaneous albinism | TYR (common)
40
creamy white skin | light blonde, yellow, or light brown hair
Type 2 (OCA2; common) and 4 (SCL45A2) oculocutaneous albinism
41
dark-skinned people with reddish-brown skin, ginger or red hair, hazel or light-brown irises
Type 3 oculocutaneous albinism | TYRP1
42
Females- plateau of development between 6-18 months followed by developmental regression, postnatal deceleration of head growth leading to microcephaly, *stereotypical hand wringing*, seizures, spasticity, breathing disturbances, sleep abnormalities, autism, absent speech Males born alive- neonatal encephalopathy and ID
Rett syndrome X-linked (most often male lethal) MECP2
43
hearing loss (conductive, SN, or mixed) abnormal ossicles frontal and occipital prominence, hypertelorism, small nose and mouth, midface hypoplasia cleft soft palate, absent or impacted teeth small trunk, pectus excavatum, small iliac crest mild ID limited elbow extension, bowing of tibia short, broad distal phalanges, most notably of thumbs and great toes, relatively short metacarpals 3-5, short nails, widely spaced toes ("tree-frog digits")
Oto-palato-digital syndrome RARE X-linked disorder of skeletal development FLNA (can also cause other conditions)
44
* hydrocephalus* due to aqueductal stenosis (leads to macrocephaly, spasticity, ID; agenesis of corpus callosum also occurs) * thumb adduction*
X-linked hydrocephalus/L1 syndrome XL L1CAM
45
prenatal and postnatal overgrowth, hemihypertrophy macroglossia ear crease and posterior pits omphalocele facial nevus flammeus neonatal hypoglycemia increased risk for embryonic tumors (Wilms, hepatoblastoma)
Beckwith-Wiedemann syndrome imprinting defect at 11p15 Domain 1 contains paternally-expressed IGF2 (maternally derived translocations and inversions, paternal UPD, imprinting anomalies) Domain 2 contains additional imprinted genes (loss of imprinting of LIT1, mutations CDKN1C can lead to AD inheritance of BWS as well) NOTE we can see BWS in one monozygotic twin (and not in the other) - especially in females; seems to happen more in ART pregnancies too
46
``` prenatal and postnatal growth restriction with head sparing growth asymmetry (especially of limbs) small, triangular face down-turned corners of mouth micrognathia cafe-au-lait macules 2-3 toe syndactyly, 5th finger clinodactyly final height up to 5 feet normal intelligence ```
Russel-Silver syndrome maternal UPD chromosome 7 (10%) Hypomethylation H19/IGF2 region on 11p15.5 (40%)
47
seizures microcephaly severe DD (notable by 6-12 months; absent speech, severe ID) happy, excitable demeanor with frequent smiling, laughing hand flapping, ataxia, jerking movements widely-spaced teeth fair skin, light colored hair and eyes (some)
Angelman syndrome loss of function of maternal UBE3A through: deletion of maternal 15q11-q13 (70%) mutation in maternal UBE3A (11%) OR paternal UPD 15 *genes for Occulocutaneous albinism can be included in the region and can result in the light hair/eyes*
48
severe hypotonia in the neonatal period, feeding difficulties in infancy with FFT DD insatiable appetite leading to hyperphagia, obesity beginning in childhood behavioral difficulties with compulsiveness, skin picking, temper outbursts bitemporal narrowing, almond shaped eyes small hands and feet underdeveloped genitals and delayed puberty fair skin and light hair and eyes (some)
Prader-Willi syndrome loss of function of genes in paternal region of 15q11-q13 through: deletion of paternal 15q11-q13 (70%) maternal UPD 15 (25%) mutation in imprinting center (rare) *genes for Occulocutaneous albinism can be included in the region and can result in the light hair/eyes
49
hypohidrosis or anhidrosis (due to reduced or absent sweat glands) - can lead to hyperthermia hypotrichosis of scalp, eyebrows, and eyelashes sparse or fine hair conical teeth, oligodontia thin skin with decreased pigmentation, papular changes on face periorbital wrinkling and hyperpigmentation
Hypohidrotic Ectodermal Dysplasia X-linked- EDA1 AD/AR- EDAR and EDARADD some other genes known as well
50
``` cleft tongue lobulated tongue tongue hamartomas hyperplastic frenulum absent, extra, or dysplastic teeth cleft palate/lip hypertelorism wide nose with broad nasal bridge polydactyly, syndactyly, brachydactyly, clinodactyly (of fingers and toes) polycystic kidneys (type I) ```
``` Oral-facial-digital syndrome RARE at least 13 types Type I: X-linked, mutations in OFD1 Others are mostly AR, many not yet well-defined, genes unknown, have overlapping features ```
51
hematuria and proteinuria leading to renal scarring and then renal failure hearing loss *anterior lenticonus* and other misshapen lenses affecting vision
Alport Syndrome X-linked mutations in COL4A5 (80%) AR (15%) or AD (5%) mutations in COL4A3 or COL4A4
52
bone marrow failure with pancytopenia (progressive) short stature microcephaly ID (in 25%) radial ray defects (hypoplasia or aplasia of thumb, supernumerary thumb, hypoplasia of radii) hypoplasitc or malformed kidneys, double ureter AML, solid tumors
Fanconi Anemia can be caused by 15+ genes most AR due to mutations in FANCA, FANCC, or FANCG One XL
53
What is a malformation?
structural difference arising from a primary localized error in morphogenesis (e.g. congenital heart defect, polydactyly, cleft palate in Van der Woude syndrome) this can be driven by genetic or teratogenic factors
54
What is a deformation?
an alteration in the shape or structure of a body part that has differentiated normally - caused by non-disruptive mechanical forces (e.g. Potter sequence, amniotic band, twin constraint, Pierre-Robin sequence)
55
What is a disruption?
structural defect resulting from destruction of a body part that has differentiated normally (e.g. amniotic band)
56
What is dysplasia?
an abnormal organization of cells into tissue as a consequence of a generalized defect in differentiation or growth (e.g. achondroplasia) you do form the tissue, however the signal is wrong and the final product is different
57
``` myopia ectopia lentis or lens subluxation retinal detachment glaucoma cataracts aortic aneurysm or other aortic dilation (Z-score >/= 2.0) - progressive (significant risk when reaches 5 cm) aortic regurgitation, mitral valve prolapse, tricuspid valve prolapse (may have secondary left ventricular dilation and failure) excess linear growth of the long bones (increased arm span to height ratio and degreased upper to lower segment ratio) pectus tall stature scoliosis or kyphosis arachnodactyly (by thumb and wrist sign) joint hypermobility hindfoot deformity/valgus pes planus protrusio acetabuli long, narrow face, deep set eyes, downslanting palpebral fissures, malar hypoplasia, micrognathia high arched/narrow palate lung bullae/spontaneous pneumothorax increased risk of hernia striae not associated with weight changes or pregnancy dural ectasia ```
Marfan syndrome AD ~25% de novo FBN1 gene (can cause other conditions as well)
58
What are the Ghent criteria?
In the absence of family history- 1. aortic diameter Z >/= 2 or aortic root dissection + ectopia lentis 2. aortic diameter Z >/= 2 or aortic root dissection + FBN1 pathogenic variant 3. aortic diameter Z >/= 2 or aortic root dissection + systemic score >/= 7 4. ectopia lentis + FBN1 pathogenic variant that has been previously identified in a related unrelated individual with aortic aneurysm With fhx- 1. ectopia lentis + fhx of Marfan syndrome 2. systemic score >/= 7 + fhx of Marfan syndrome 3. aortic diameter Z >/=2 (above age 20) or Z >/= 3 (below age 20) + fhx of Marfan syndrome
59
What is the systemic score for Marfan syndrome as defined by the Ghent critieria?
``` Wrist and/or thumb sign (3 for both or 1 each) Pectus caranatum (2) Pectus excavatum/chest asymmetry (1) Hindfoot deformity (2) Pes planus (1) Pneumothorax (2) Dural ectasia (2) Protrusio acetabuli (2) Reduced upper segment to lower segment ratio AND increased armspan to height ratio AND no severe scoliosis (1) Scoliosis or thoracolumbar kyphosis (1) Reduced elbow extension (1) Facial features -at least three- (1) - dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia Skin striae (1) Myopia > 3 diopters (1) Mitral valve prolapse (1) ```
60
What conditions do mutations in FBN1 cause?
``` Marfan Syndrome MASS phenotype thoracic aortic aneurysm and aortic dissection (TAAD) Familial isolated ectopia lentis Stiff skin syndrome Weill-Marchesani Geleophysic dysplasia 2 Acromicric dysplasia Marfan lipodystrophy syndrome ```
61
What are the recommended evaluations and management strategies for a patient diagnosed with Marfan syndrome?
opthalmologist visits annually (with someone experienced with Marfan) myopia correction screenings for glaucoma and cataracts orthopedic follow-ups for scoliosis and pectus ECHO at dx and 6 months after - repeated annually if stable and at increased frequency if diameter >4.5 cm or rate exceeds 0.5 cm/year (in which case surgical repair may be indicated) intermittent CT/MRA for aorta surveillance initiation of beta-blockers or ARBs avoidance of high intensity sports Counseling regarding risk of aortic dissection during pregnancy (with consideration of regular ECHOs)
62
Describe the inheritance of Cystic Fibrosis.
AR (but requires clinical dx of sweat chloride testing >60 mmol/L Cl- AND clinical features) CFTR gene - F508del variant in ~90% of individuals R117H variant is modified by the polyT tract (R117H with 5T results in more severe phenotype than R117H with 7T and R117H with 9T is unlikely to show clinical symptoms but may be at risk for CBAVD) PolyT tract is modified by TGs (5T with TG11 is less severe than 5T with TG12 and 5T with TG13 is most severe)
63
``` chronic lung infections, inflammation, and obstruction recurrent sinusitis decreased lung function (progressive) pancreatic insufficiency failure to thrive vitamin deficiency meconium ileus osteopenia/osteoporosis diabetes liver disease salty sweat degraded vas deferans difficulty conceiving in females (due to thickened cervical mucus) Fetal Echogenic Bowel and/or intestinal dilation ```
Cystic Fibrosis AR CFTR (see other card for specific variants)
64
What are the management and treatment recommendations for patients with Cysitc Fibrosis?
``` antibiotics (inhaled/IV/oral) Bronchodilators mucolytics (dornase alpha) anti-inflammatories airway clearance therapies lung transplantation (considered when FEV1 falls below 30%) pancreatic enzyme replacement high calorie/protein diet vitamin supplements DEXA screening diabetes management ```
65
Describe the classification of CFTR variants.
``` Classic (severe): Class I - unstable mRNA and no functional protein Class II - trafficking and processing defects Class III - defective gating regulation Mild/Moderate: Class IV - decreased conductance Class V - reduced protein quantity Class VI - decreased protein stability ```
66
Asymptomatic Intermediate sweat chloride (30-59 mmol/L) <2CF-causing CFTR variants OR two CFTR variants in trans (at least one of unclear significance; sweat Cl- <30)
CFTR-Related Metabolic Syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID)
67
Describe CFTR modulator therapies.
Potentiator (ivacaftor)- helps to open the 'gate' of the CFTR channel to allow ion flow; e.g. G551D Correctors (lumacaftor, texacaftor, elexacaftor)- helps to stabilixe misfolded CFTR protein so that it can be properly trafficked to the cell membrane; e.g. F508del CAN'T treat variants expected to result in no CFTR protein production (though some non-modulator treatments for this are in trials)
68
``` bronchiectasis pancreatitis (acute, recurrent, or chronic) CBAVD sinusitis, asthma sweat chloride typically <60 mmol/L later onset ```
CFTR-related disorder
69
Describe the different kinds of transmission through families seen on pedigrees.
Vertical- phenotype seen in generation after generation (often associated with AD or XL with "skipped generations" or Y linked) Horizontal- phenotype seen in siblings but not previous generations (often associated with AR)
70
Define reduced penetrance.
individual with a disease-associated genotype may not have the disease phenotype BUT offspring are still at risk
71
Define variable expression/expressivity.
severity of the phenotype varies widely, even within a family an individual's presentation may be so mild that they are not aware that they are affected and can pass on the condition to their children environmental exposures and modifier genes may influence variable expression within families
72
Define phenocopies.
an individual with a similar phenotype does not have the disease-causing gene, and their phenotype is cause by another factor
73
What is MASS phenotype?
ADULTS > age 20 with some Marfan syndrome features ( systemic score >/=5; NO ectopia lentis) Mitral valve prolapse borderline (but not progressive) Aortic dilation (Z <2) Striae Skeletal feature(s)- at least one- (excess linear growth of the long bones -increased arm span to height ratio and degreased upper to lower segment ratio-, pectus, tall stature, scoliosis or kyphosis, arachnodactyly, joint hypermobility, hindfoot deformity/valgus, pes planus, protrusio acetabuli)

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