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Conditions Flashcards

1
Q

Achondroplasia gene

A

FGFR3

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2
Q

Achondroplasia inheritance

A

AD; 80% de novo

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3
Q

Achondroplasia description

A

Rhizomelic shortening, macrocephaly, apnea, obesity, ear infections, genu verum (leg bowing), lordosis, kyphosis, spinal stenosis, hydrocephalus
Average lifespan

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4
Q

Achondroplasia mutation(s)

A 
GoF (constitutive activation)
Two mutations:
• c.1138G>A (p.Gly380Arg)
• c.1138G>C (p.Gly380Arg)
Penetrance 100%
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5
Q

Hypochondroplasia gene

A

FGFR3 (~70%)

Potentially others too

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6
Q

Hypochondroplasia inheritance

A

AD; majority de novo

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7
Q

Hypochondroplasia description

A

Features similar to achondroplasia, but milder. Rhizo or meso.
May have mild ID
Average lifespan

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8
Q

Thanatophoric Dysplasia gene

A

FGFR3

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9
Q

Thanatophoric Dysplasia inheritance

A

AD; ~100% de novo

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10
Q

Thanatophoric Dysplasia description

A

Micromelia, redundant skin, narrow chest, short ribs, under-developed lungs, macrocephaly, platyspondyly (flat vertebral bodies)
Type I: curved thigh bones
Type II: straight thigh bones and a moderate to severe cloverleaf skull
Typically lethal

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11
Q

Campomelic Dysplasia gene

A

SOX9

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12
Q

Campomelic Dysplasia inheritance

A

AD; most de novo

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13
Q

Campomelic Dysplasia description

A

Short & bowed legs, dislocated hips, club feet, missing ribs, ambiguous genitalia, Pierre Robin.
Often lethal in infancy

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14
Q

Diastrophic Dysplasia gene

A

SLC26A2

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15
Q

Diastrophic Dysplasia inheritance

A

AR

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16
Q

Diastrophic Dysplasia description

A

Short limbs, osteoarthritis, contractures, club foot, scoliosis, thumb abnormalities, cleft palate.
Typically live to adulthood

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17
Q

SMA gene

A

SMN1, SMN2

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18
Q

SMA inheritance

A

AR

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19
Q

SMA description

A

Loss of lower motor neurons -> muscle atrophy
Proximal > distal progressive weakness, restrictive lung disease, joint contractures, scoliosis, tongue fasciculations (twitches). Types 0-IV correspond to # of SMN2 generally.

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20
Q

SMN Testing

A

SMN1 exon 7 del/dup (up to 98% of cases), followed by SMN1 sequencing (2-5%)

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21
Q

Charcot Marie Tooth gene

A

Many, including PMP22 (CMT1A)

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22
Q

Charcot Marie Tooth inheritance

A

Type 1 & 2: AD
Type 4: AR
Many more forms, including X-linked

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23
Q

Charcot Marie Tooth description

A

Peripheral nerve damage. Progressive distal weakness, foot drop, loss of sensory nerve function, shortened achilles, atrophy, contractures, hearing loss

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24
Q

Charcot Marie Tooth Testing

A

Can start with PMP22 del/dup. Next, gene panel. Nerve conduction studies and nerve bx.

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25
Q

Dystrophinopathies gene

A

DMD

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26
Q

Dystrophinopathies inheritance

A

X-linked

1/3 de novo

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27
Q

Dystrophinopathies description

A

Proximal atrophy, DCM

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28
Q

Dystrophinopathies Testing

A

Elevated CK, molecular testing (del/dup then sequence)

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29
Q

Myotonic Dystrophy gene

A

Type I: DMPK
Type II: ZNF9
Both repeat expansion disorders

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30
Q

Myotonic Dystrophy inheritance

A

AD with anticipation

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31
Q

Myotonic Dystrophy description

A

Distal, diaphragm, neck, and face muscle weakness, cataracts, intellectual impairment, arrhythmia, cardiomyopathy, GI issues, balding, “pregnancy and gyn problems,” male infertility. Type II less severe.

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32
Q

Myotonic Dystrophy testing

A

PCR or Southern Blot

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33
Q

Facioscapulohumeral Muscular Dystrophy Gene

A

D4Z4

Microsatellite contraction disorder

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34
Q

Facioscapulohumeral Muscular Dystrophy inheritance

A

AD

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35
Q

Facioscapulohumeral Muscular Dystrophy description

A

Muscle weakness of face, shoulders, upper arms. Other features: hearing loss, retinal telangiectasias

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36
Q

Emery-Dreifuss Muscular Dystrophy gene

A

Many, including EMD and LMNA

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37
Q

Emery-Dreifuss Muscular Dystrophy inheritance

A

Majority X-linked or AD

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38
Q

Emery-Dreifuss Muscular Dystrophy description

A

Weakness of shoulders, upper arms, calves; contractures in elbows, neck, ankles; conduction block in heart. Onset by 10y

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39
Q

Friedreich’s Ataxia gene

A

FXN

Repeat expansion disorder in nuclear mt gene

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40
Q

Friedreich’s Ataxia inheritance

A

AR

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41
Q

Friedreich’s Ataxia description

A

Impaired coordination, spasticity, arm/leg weakness, impaired hearing/speech/vision, hypertrophic cardiomyopathy. Onset typically 5-15y

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42
Q

Spinocerebellar Ataxia (SCA) Type I, II, III, etc. gene

A

ATXN1, ATXN2, ATXN3, etc. (CAG repeat)

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43
Q

Spinocerebellar Ataxia (SCA) Type I, II, III, etc. inheritance

A

AD; anticipation (paternal allele expansion)

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44
Q

Spinocerebellar Ataxia (SCA) Type I, II, III, etc. description

A

Progressive cerebellar ataxia, dysarthria, gait disturbance, slurred speech, difficulty with balance

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45
Q

Rett gene

A

MECP2

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46
Q

Rett inheritance

A

X-linked dominant

Almost all de novo

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47
Q

Rett description

A

Almost exclusively females.
Onset: 6-18m
Loss/impairment of language, communication, coordination. Stereotypes hand movements. Abnormal breathing patterns. Seizure.
Life expectancy ~40s

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48
Q

MECP2 duplication syndrome inher.

A

x-linked

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49
Q

MECP2 duplication syndrome desc.

A

“Almost exclusively males.

ID, hypotonia, seizures, respiratory tract infections.”

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50
Q

Canavan gene

A

ASPA

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51
Q

Canavan inher.

A

AR

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52
Q

Canavan desc.

A

Leukodystrophy. Fail to meet early motor milestones, hypotonia, macrocephaly, seizures. Typically die in childhood.

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53
Q

Familial dysautonomia gene

A

ELP1 (aka IKBKAP)

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54
Q

Familial dysautonomia inher.

A

AR

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55
Q

Familial dysautonomia desc.

A

Affects autonomic (involuntary) system and sensory nervous system. Onset infancy. Hypotonia, poor growth, lack of tears, lung infections, temperature dysregulation, abnormal breathing patterns, blood pressure dysregulation, optic atrophy

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56
Q

Apo Alleles

A

“E4: risk conferring, but not necessary or sufficient for disease
E2: protective
E3: neutral”

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57
Q

Alzheimers (early-onset, AD) gene

A

APP, PSEN1, PSEN2

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58
Q

Frontotemporal dementia (AD) gene

A

MAPT and others

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59
Q

Frontotemporal dementia inher.

A

~50% sporadic
~30% familial
~20% AD

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60
Q

Frontotemporal dementia (AD) desc.

A

“Behavioral Variant (bvFTD)
Disinhibition, apathy, compulsive, diminished executive functioning
Primary Progressive Aphasia
Non-fluent type: motor speech problems
Semantic type: loss of word meaning
Behavioral changes, parkinsonism, eventually mute”

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61
Q

Lewy Body Dementia gene

A

SNCA, SNCB

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62
Q

Lewy Body Dementia inher.

A

AD

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63
Q

Lewy Body Dementia desc.

A

Dementia, parkinsonism, hallucinations, fluctuations in behavior and intellect, REM sleep disorder

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64
Q

CADASIL gene

A

NOTCH3

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65
Q

CADASIL inher.

A

AD

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66
Q

CADASIL desc.

A

“Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Migraines, TIAs, psychiatric
Variable onset”

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67
Q

Waardenburg gene

A

PAX3, MITF, SOX10, SNAI2

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68
Q

Waardenburg inher.

A

ad

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69
Q

Waardenburg desc.

A

“Congenital SNHL (20-50% of pt), dystopia canthorum (pupils close set), heterochromia, blue eyes, white forelock, vitiligo, Hirschsprung disease
4 subtypes”

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70
Q

Usher gene

A

Type 1: MYO7A (~50%) and many others

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71
Q

Usher inher.

A

AR

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72
Q

Usher desc.

A

“Type 1: Congenital SNHL, vestibular dysfunction causes delayed milestones (walking, etc), adolescent onset RP
Type 2: Normal vestibular function
Type 3: Progressive/post lingual SNHL, late onset RP, variable vestibular function”

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73
Q

Jervell and Lange-Nielson syndrome gene

A

KCNQ1 and KCNE1

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74
Q

Jervell and Lange-Nielson syndrome inher.

A

AR

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75
Q

Jervell and Lange-Nielson syndrome desc.

A

Congenital SNHL, long QT, childhood fainting

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76
Q

Pendred gene

A

SLC26A4 (50%)

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77
Q

Pendred inher.

A

AR

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78
Q

Pendred desc.

A

Congenital SNHL, vestibular dysfunction, temporal bone abnormalities, goiter

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79
Q

BORS/ BOS gene

A

EYA1 and others

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80
Q

BORS/ BOS inher.

A

AD

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81
Q

BORS/ BOS desc.

A

Variable onset of conductive, SN, or mixed HL, branchial cysts, various renal anomalies, variable expressivity

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82
Q

Meckel Gruber syndrome gene

A

Many proposed. Ciliopathy

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83
Q

Meckel Gruber syndrome inher.

A

AR

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84
Q

Meckel Gruber syndrome desc.

A

Occipital encephalocele, cystic kidneys, postaxial polydactyly

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85
Q

Alport gene

A

COL4A3/COL4A4/COL4A5

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86
Q

Alport inher

A

2/3 x-linked, then AR and AD

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87
Q

Alport desc.

A

“Hallmark: microhematuria.
Renal prgression: hematuria, proteinuria, hypertension, renal insufficiency.
Progressive SNHL ~late childhood
Anterior lenticonus (pathognomonic, teens-20s in 15% of males), other eye anomalies
Female “carriers” can have renal disease
60% of males reach ESRD by 30y”
AD has later onset, no eye stuff

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88
Q

Autosomal Recessive Polycystic Kidney Disease gene

A

PKHD1

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89
Q

Autosomal Recessive Polycystic Kidney Disease desc.

A

Bilateral, microcysts
Liver involvement- cysts, hepatomegaly
If survive first year, 50% have ESRD by 10y

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90
Q

Autosomal Dominant Polycystic Kidney Disease gene

A

PKD1 (85%)

PKD2 (15%)

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91
Q

Autosomal Dominant Polycystic Kidney Disease desc.

A 
Adult onset (20s-30s), multisystem
Bilateral renal cysts, cysts in other organs (esp. liver), vascular anomalies (hypertension, aneurysm, etc)
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92
Q

FMR1-Related Disorders inher.

A

X-linked with maternal expansion. Anticipation

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93
Q

FMR1-Related Disorders molecular info

A 
CGG repeat in 5’ UTR
Normal: 5-44
Intermediate: 45-54
Premutation: 55-200
Full: >200
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94
Q

FMR1-Related Disorders desc.

A

DD, ID, behavioral issues, autism, hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, recurrent otitis media, mitral valve prolapse, aortic root dilatation, macroorchidism.
Premutation risk for FXTAS and FXPOI

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95
Q

Huntington Disease gene

A

HTT

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96
Q

Huntington Disease molecular info

A 
"CAG repeat (polyglutamine disease)
Normal: <26
Intermediate: 27-35
Reduced Penetrance: 36-39
Full Penetrance: >40"
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97
Q

Huntington Disease inher.

A

AD with paternal expansion. Anticipation

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98
Q

Huntington Disease desc.

A

Coordination issues, chorea, depression, personality changes, delusions, speech difficulties, dysarthria, dysphagia

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99
Q

Spinal and Bulbar Muscular Atrophy gene

A

AR (androgen receptor)

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100
Q

Spinal and Bulbar Muscular Atrophy inher.

A

x-linked

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101
Q

Spinal and Bulbar Muscular Atrophy molecular info

A 
"CAG repeat (polyglutamine disease)
More repeats = early onset and progression
< 34 = normal
> 38 = full penetrance
Repeat number fairly stable"
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102
Q

Spinal and Bulbar Muscular Atrophy desc.

A

“Feminization onset in adolescence (males)
Neuromuscular onset 30s-50s
Bulbar disease (fasciculations of the tongue, lips, or perioral region; dysarthria; dysphagia)
Spinal lower motor neuron disease

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103
Q

Myotonic dystrophy molecular info

A 
"Type 1: CTG
Type 1: 150-1,000 repeats
Type 1 congenital: >1,000 repeats
Type 2: CCTG
Type 2: 75-11,000 repeats"
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104
Q

Friedreich’s Ataxia molecular info

A

“GAA repeat in nuclear mt gene
Normal: 5-33
Fully penetrant: >66”

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105
Q

Congenital Adrenal Hyperplasia gene

A

CYP21A2 (~95%), CYP11B1 (~5%)

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106
Q

Congenital Adrenal Hyperplasia inher.

A

AR

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107
Q

Congenital Adrenal Hyperplasia desc. for CYP21A2:

A 
For CYP21A2: 
1) Classic
a) Salt-wasting (~75%)
Females with ambiguous genitalia
b) Simple virilizing
No salt loss
Females with ambiguous genitalia
2) Non-classic
Females with normal genitalia
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108
Q

Androgen Insensitivity Syndrome gene

A

AR

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109
Q

Androgen Insensitivity Syndrome inher.

A

X-linked

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110
Q

Androgen Insensitivity Syndrome desc.

A

CAIS- external female genitalia

PAIS- spectrum of genital phenotype

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111
Q

Smith-Lemli-Opitz syndrome gene

A

DHCR7 (7-dehydrocholesterol reductase)

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112
Q

Smith-Lemli-Opitz syndrome inher.

A

AR

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113
Q

Smith-Lemli-Opitz syndrome desc.

A

Growth retardation, microcephaly, ID, cleft palate, cardiac defects, most have toe syndactyly, polydactyly, underdeveloped male genitalia

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114
Q

Cytochrome P450 oxidoreductase deficiency gene

A

POR

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115
Q

Cytochrome P450 oxidoreductase deficiency inher.

A

AR

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116
Q

Cytochrome P450 oxidoreductase deficiency desc.

A

Phenotypic range affecting reproductive organs and skeleton.

Severe form also called Antley-Bixler Syndrome

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117
Q

Long QT gene

A

LQT1: KCNQ1
LQT2: KCNH2
LQT3: SCN5A
and others

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118
Q

Long QT inher.

A

Mostly AD

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119
Q

Long QT desc.

A

Onset often teens/20s,
LQT1: Exercise, emotion
LQT2: Noise, emotion
LQT3: Sleep

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120
Q

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) gene

A

RYR2, CALM1 (AD)

CASQ2, TRDN (AR)

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121
Q

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) inher.

A

RYR2, CALM1 (AD)

CASQ2, TRDN (AR)

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122
Q

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) desc.

A

“Tachycardia triggered by stress (exercise, emotion)

Typically childhood onset”

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123
Q

Brugada gene

A

Many, including SCN5A (~15-30%)

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124
Q

Brugada inher

A

AD

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125
Q

Brugada desc.

A

Na channelopathy
Ventricular arrhythmia, ST segment abnormalities. Brugada pattern can lead to an arrhythmia, which can lead to fibrillation, which can lead to syncope and/or arrest. Can induce pattern with exercise

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126
Q

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) gene

A

Many, including PKP2 . Many are desmosomal genes (cell to cell adhesion and signalling)

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127
Q

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) inher.

A

Most AD

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128
Q

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) desc.

A

Replacement of myocardium with fibrofatty tissue

Restrict exercise b/c accelerates replacement

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129
Q

Hypertrophic Cardiomyopathy (HCM) gene

A

MYH7, MYBPC3, others

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130
Q

Hypertrophic Cardiomyopathy (HCM) inher.

A

Most AD

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131
Q

Hypertrophic Cardiomyopathy (HCM) desc.

A

LVH with heritable component

Most common cause of sudden cardiac death in young athletes

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132
Q

Dilated Cardiomyopathy (DCM) gene

A

TTN, LMNA, MYH6, MYH7, others

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133
Q

Dilated Cardiomyopathy (DCM) inher.

A

AD, AR, X-linked

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134
Q

Left Ventricular Noncompaction (LVNC) gene

A

MYH7 or MYBPC3 (~30%) or others

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135
Q

Left Ventricular Noncompaction (LVNC) inher.

A

Most AD

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136
Q

Left Ventricular Noncompaction (LVNC) desc.

A

Cardiac muscle in left ventricle is thick and appears spongy. Symptoms: palpitations, blood clots, arrhythmia, exercise intolerance, shortness of breath, fainting, lymphedema, SCD

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137
Q

Familial TAAD gene

A

ACTA2 (~15%)

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138
Q

Familial hypercholesterolemia gene

A

LDLR, APOB, PCSK9 and others

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139
Q

Familial hypercholesterolemia inher

A

Most AD

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140
Q

Familial hypercholesterolemia desc.

A

Cholesterol build up increases risk of heart disease. Xanthomas (cholesterol deposits) can occur around the eyelids and within tendons of the elbows, hands, knees, and feet. Homozygotes or compound heterozygotes have adolescent onset

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141
Q

OI gene

A

COL1A1 and COL1A2 (90%) and many others

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142
Q

OI inher.

A

AD for COL1A1 and COL1A2

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143
Q

OI molecular

A

Type I: Quantitative mutations
LoF variants. Often premature stop codons
Type II, III, IV: Qualitative mutations. Dominant negative. Typically substitution of a glycine

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144
Q

OI “type I”

A

Classic non-deforming OI with blue sclera (Type I): Mild, normalish stature, no DI, blue sclera, 50% hearing loss, wormian bones

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145
Q

OI “type II”

A

Perinatally lethal OI (Type II): Severe, very short stature, DI, dark blue sclera, small beaded ribs (pathognomonic), minimal calvarial mineralization, platyspondyly

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146
Q

OI “type III”

A

Progressively deforming OI (Type III): Severe, very short stature, DI, blue sclera, frequent hearing loss, thin bones, platyspondyly, wormian bones

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147
Q

OI “type IV”

A

Common variable OI with normal sclera (Type IV): Mild to moderate, variable stature, +/- DI, normal to grey sclera, variable hearing loss, +/- wormian bones

148
Q

Loeys-Dietz gene

A

TGFBR1, TGFBR2, TGFB2, SMAD3

149
Q

Loeys-Dietz inher.

A

AD

150
Q

Loeys-Dietz desc.

A

Vasculature tortuosity, aneurysms, dissections (aortic and other), pectus excavatum or carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, hypertelorism, bifid uvula, cleft palate, craniosynostosis, translucent skin, atrophic scars, easy bruising, uterine rupture, spontaneous pneumothorax, hernias

151
Q

Stickler Syndrome gene and mech

A

COL2A1 (80-90%), COL11A1 (10-20%), and others

COL2A1: premature stop resulting in haploinsufficiency

152
Q

Stickler Syndrome inher.

A

AD (AR forms also exist)

153
Q

Stickler Syndrome desc.

A

Ocular: myopia, cataract, retinal detachment
Hearing loss: conductive and sensorineural
Cleft palate (pierre robin), midface hypoplasia, mild spondyloepiphyseal dysplasia and/or precocious arthritis, MVP (but no aneurysm stuff). Think: eyes, ears, joints

154
Q

Marfan Syndrome gene and mech

A

FBN1
25-35% de novo
dominant negative

155
Q

Marfan Syndrome inher

A

AD

156
Q

Marfan Syndrome desc.

A

Tall, thin, prominent brow, micrognathia, myopia, lens dislocation or abnormalities, stretch marks, hernia, aortic root dilation, mitral valve prolapse, pneumothorax, dural ectasia, long long bones, pectus deformities, scoliosis, pes planus, arachnodactyly, dental crowding, hypermobility

157
Q

Ehlers Danlos Syndrome classic gene

A

Classic: COL5A1, COL5A2

158
Q

Ehlers Danlos Syndrome classic inher

A

AD

159
Q

Ehlers Danlos Syndrome classic desc.

A

Velvety, elastic skin, bruise easily, paper scarring, poor healing, joint dislocations and subluxations, chronic pain, pregnancy complications, decreased aortic stiffness

160
Q

vascular eds gene

A

Vascular: COL3A1

161
Q

vascular eds inher

A

AD

162
Q

vascular eds desc.

A

Aneurysms; arterial, intestinal, uterine rupture; thin, translucent, inelastic skin

163
Q

Van der Woude gene

A

IRF6

164
Q

Van der Woude inher.

A

AD

165
Q

Van der Woude desc.

A

Mixed clefting, lip pits

166
Q

Witkop gene

A

MSX1

167
Q

Witkop inher.

A

AD

168
Q

Witkop desc.

A

Nail dysplasia, missing teeth

169
Q

Kallmann gene

A

ANOS1

170
Q

Kallmann inher.

A

X-linked (ANOS1)
AD (FGFR1 and others)
AR (others)

171
Q

Kallmann desc.

A

Hypogonadotropic hypogonadism (delayed/absent puberty), impaired sense of smell, CL +/- CP, unilateral renal agenesis, hearing loss, dental anomalies

172
Q

Ectrodactyly Ectodermal dysplasia gene

A

TP63

173
Q

Ectrodactyly Ectodermal dysplasia inher

A

AD

174
Q

Ectrodactyly Ectodermal dysplasia desc

A

CL +/- CP, cleft hands/feet, light hair, light eyes

175
Q

CHARGE gene and mech

A

CHD7, Involved in chromatin remodeling.

176
Q

CHARGE inher

A

Most de novo. AD

177
Q

CHARGE desc

A

Coloboma, heart defects, choanal atresia, retarded growth, genitalia, ear anomalies, CL +/- CP

178
Q

Treacher Collins gene

A

TCOF1

179
Q

Treacher Collins inher

A

AD, 60% de novo

180
Q

Treacher Collins desc

A

CP (~25%), hypoplasia of zygomatic and mandibular bones, ear abnormalities, hearing loss, vision problems, eyelid notch

181
Q

Apert gene

A

FGFR2

182
Q

Apert mech and inher

A

AD
GoF mutations
Advanced paternal age
Almost all de novo

183
Q

Apert desc

A

Coronal (+/- other) craniosynostosis, hand differences (bone fusion, syndactyly), cleft palate (30%), bifid uvula, high broad forehead, mandibular prognathism, ~50% ID

184
Q

Crouzon gene

A

FGFR2, FGFR3

185
Q

Crouzon mech and inher

A

AD

Advanced paternal age

186
Q

Crouzon desc.

A

Craniosynostosis (any), frontal bossing, hydrocephalus, mandibular prognathism, normal intellect

187
Q

Muenke gene

A

FGFR3

188
Q

Muenke mech and inher

A

AD
GoF mutations
Advanced paternal age
de novo rate unknown

189
Q

Muenke desc

A

Very variable. Various craniosynostoses, carpal-tarsal fusion diagnostic when present

190
Q

Pheiffer gene

A

FGFR1, FGFR2

191
Q

Pheiffer inher

A

AD, Advanced paternal age

192
Q

Pheiffer desc

A

Coronal w or w/o sagittal, occasional clover leaf skull, hydrocephalus, broad thumb and broad big toe, range of ID

193
Q

Saethre-Chotzen gene

A

TWIST

194
Q

Saethre-Chotzen inher and mech

A

AD
Haploinsufficiency
de novo rate unknown

195
Q

Saethre-Chotzen desc

A

Coronal, facial asymmetry

196
Q

Cleidocranial dysplasia gene and mech

A

RUNX2, haploinsufficiency

197
Q

Cleidocranial dysplasia inher

A

AD

198
Q

Cleidocranial dysplasia desc

A

Delayed ossification of skull, open cranial sutures, wormian bones, hypoplastic clavicles, teeth differences

199
Q

NF1 gene and mech

A

NF1
Haploinsufficiency of neurofibromin causes activation of Ras/MAPK pathway
NF1 is tumor suppressor gene

200
Q

NF1 inher

A

“AD
50% de novo
Variable expressivity”

201
Q

NF1 desc

A

CALMs; intertriginous freckling; neurofibromas and plexiform neurofibromas; iris Lisch nodules; osseous dysplasia; optic pathway glioma; nl neurocognitive function or mild impairment.
Pediatric cancers: optic pathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia
Adult cancers: malignant peripheral nerve sheath tumors, GIST, somatostatinomas, pheochromocytomas, breast cancer

202
Q

Legius gene

A

SPRED1

203
Q

Legius inher and mech

A

AD, LoF -> Dysregulated pathway

204
Q

Legius desc

A

Like NF1, except no neoplastic features (neurofibromas, plexiform neurofibromas, iris Lisch nodules, and CNS tumors)

205
Q

Noonan gene

A

PTPN11, KRAS, SOS

206
Q

Noonan inher

A

“AD
Many de novo”
activation of pathway

207
Q

Noonan desc

A

Craniofacial dysmorphic features; congenital heart defects; short stature; undescended testicles; ophthalmologic abnormalities; bleeding disorders; nl neurocognitive function or mild impairment; predisposition to cancer

208
Q

Noonan with Multiple Lentigines gene

A

PTPN11, CRAF1/RAF1

209
Q

Noonan with Multiple Lentigines inher

A

AD

210
Q

Noonan with Multiple Lentigines desc

A

Same as Noonan syndrome, but with possible development of multiple skin lentigines as individuals age; unclear predisposition to cancer

211
Q

Capillary Malformation–Arteriovenous Malformation Syndrome gene

A

RASA1

212
Q

Capillary Malformation–Arteriovenous Malformation Syndrome inher and mech

A

“AD
30% de novo”
Hapolinsufficiency -> pathway activation

213
Q

Capillary Malformation–Arteriovenous Malformation Syndrome desc.

A

Multifocal capillary malformations, which may be associated with arteriovenous malformations and fistulae

214
Q

Costello gene

A

HRAS

215
Q

Costello inher and mech

A

“AD
Almost all de novo”
activation of pathway

216
Q

Costello desc

A

Coarse features; congenital heart defects; failure to thrive; short stature; ophthalmologic abnormalities; multiple skin manifestations, including papilloma; hypotonia; predisposition to cancer (rhabdomyosarcoma, neuroblastoma, transitional Cell carcinoma)

217
Q

Cardio-Facio-Cutaneous Syndrome gene

A

BRAF, MEK1, MEK2, KRAS

218
Q

Cardio-Facio-Cutaneous Syndrome inher and mech

A

“AD
Almost all de novo”
activation of pathway

219
Q

Cardio-Facio-Cutaneous Syndrome desc

A

Congenital heart defects; failure to thrive; short stature; ophthalmologic abnormalities; ectodermal findings including sparse, curly hair with sparse eyebrows and eyelashes, hyperkeratosis, keratosis pilaris, hemangioma, ichthyosis, and progressively forming nevi

220
Q

NF2 gene

A

NF2

221
Q

NF2 inher and mech

A 
"AD
50% de novo
Many pt's mosaic"
"Protein: merlin
Nonsense and frameshift often severe disease; missense often mild disease; deletions often mild disease
Part of Hippo pathway"
222
Q

NF2 desc

A

“Avg onset: 20y
Bilateral vestibular schwannomas by 30y (sx: tinnitus, hearing loss, and balance dysfunction). Spinal tumors, meningioma, schwannoma, glioma (CNS), specific cataracts, retinal hamartomas
Feature in childhood: Mononeuropathy (frequently presents as a persistent facial palsy or hand/foot drop)
Avoid radiation tx. “

223
Q

Schwannomatosis gene

A

SMARCB1, LZTR1

224
Q

Schwannomatosis inher and mech

A

Most sporadic, but ~20% familial, tumor suppressor genes

225
Q

Schwannomatosis desc

A

“Typically adult onset

Schwannomas -> numbness, weakness, tingling, pain, headaches”

226
Q

Hemochromatosis (Type 1) gene

A

HFE

227
Q

Hemochromatosis (Type 1) inher and mech

A

AR
LoF
60%-90% of Euro ancestry cases homozygous for p.Cys282Tyr
Penetrance of biochemical pheno higher than penetrance of clinical pheno
1/10 euro ancestry carriers

228
Q

Hemochromatosis (Type 1) desc

A

“Iron overload. Fatigue, joint pain, abdominal pain, arthritis, cirrhosis, liver cancer, diabetes, heart abnormalities, skin discoloration, shortage of sex hormones
Onset in men 40s-60s, in women after menopause
Tx: phlebotomy”

229
Q

Hereditary Hemorrhagic Telangiectasia gene

A

ACVRL1, ENG, (SMAD4 but only 1-2%)

230
Q

Hereditary Hemorrhagic Telangiectasia inher and mech

A

AD
All genes in TGF-β signaling pathway
De novo rare

231
Q

Hereditary Hemorrhagic Telangiectasia desc

A

“Arteriovenous malformations (AVMs) lack intervening capillaries -> direct connections between arteries and veins.
Epistaxis (nosebleeds, onset ~12y), telangiectases (small AVMs) on mouth, face, chest, fingers, GI bleeding (onset >50y).
Large AVMs in lung (esp. pregnancy), liver, or brain (congenital) are serious”

232
Q

Acute intermittent porphyria gene

A

HMBS

233
Q

Acute intermittent porphyria inher and mech

A

AD
Penetrance <1%
LoF
Reduced activity of the enzyme porphobilinogen deaminase (in the heme biosynthetic pathway)

234
Q

Acute intermittent porphyria desc

A

“Life-threatening acute neurovisceral attacks: severe abdominal pain, vomiting, tachycardia, hypertension, mental changes, convulsions, peripheral neuropathy that may progress to respiratory paralysis, and hyponatremia (low Na)
Increased risk of liver cancer, >50y”

235
Q

Factor V Leiden gene

A

F5

236
Q

Factor V Leiden mech

A

“c.1691G>A
Not susceptible to Protein C, so inactivated more slowly (leading to prolonged clotting)
~5% of Euro. ancestry are hets”

237
Q

Factor V Leiden desc

A

Thrombophilia. VTE in ~1% (of pregnancies?) in women who are Leiden variant heterozygotes (gen pop background 0.1%). Risk up to ~10% in homozygotes. Esp during pregnancy

238
Q

Prothrombin Thrombophilia gene

A

F2

239
Q

Prothrombin Thrombophilia mech

A

“c.*97G>A, aka 20210G>A

GoF mutation in the 3’UTR”

240
Q

Prothrombin Thrombophilia desc

A

The risk for recurrent VTE in homozygotes is not well defined, but presumed to be higher than in heterozygotes

241
Q

Hemophilia A gene

A

F8

242
Q

Hemophilia A inher and mech

A

X-linked
“15% de novo
Genotype-phenotype correlation: males in same family similarly affected
Intron 22 inversions account for 45% of severe cases
Missense -> mild/moderate”

243
Q

Hemophilia A desc

A

“Severity depends on amount of functional factor VIII.

~30% of heterozygous females have clotting activity below 40% and are at risk for bleeding”

244
Q

Hemophilia B gene

A

F9

245
Q

Hemophilia B inher and mech

A

X-linked
“Genotype-phenotype correlation: males in same family similarly affected
Missense often severe (unlike F8)”

246
Q

Hemophilia B desc

A

“Severity depends on amount of functional factor IX.
~30% of heterozygous females have clotting activity below 40% and are at risk for bleeding.
Unlike factor VIII, maternal factor IX does not increase in pregnancy. More likely to need factor infusion during/after delivery. “

247
Q

Von Willebrands gene

A

VWF

248
Q

Von Willebrands inher and mech

A

“Types 1 and 2 mostly AD
Type 3 AR”
Quantitative or qualitative changes to Von Willebrand Factor

249
Q

Von Willebrands desc

A

Mucocutaneous bleeding. Type 3 severe and can have musculoskeletal bleeding. Increased bleeding risk during/after birthing.

250
Q

Alpha Thal gene

A

HBA1, HBA2 (mRNA identical except 3’UTR)

251
Q

Alpha Thal mech

A

“Deletions most common variants
Non-deletion mutations tend to be more severe (eg HbH-constant spring)
beta trait can mask alpha trait”

252
Q

Alpha Thal desc

A

“Alpha thal major / HbBart syndrome: no functioning alpha-globin genes. Typically stillbirth. Maternal risks.
Hemoglobin H disease: 1 functioning alpha-globin gene. Variable. Life-long mild to moderate anemia.
Alpha thal trait: 2 functioning alpha-globin genes. Healthy. Microcytosis. May be in cis (more Asian) or trans (more AA).
Silent carrier: 3 functioning alpha-globin genes. Healthy. MCV typically nl.”

253
Q

Beta Thal gene

A

HBB

254
Q

Beta Thal mech and inher

A

AR
“No deletional mutations
beta trait can mask alpha trait”

255
Q

Beta Thal desc

A

“Severity of beta thal syndromes depends on extent of imbalance between alpha and non-alpha chains being produced
Beta Thal Major- regular blood transfusions
Beta Thal Intermedia- transfusion rarely required
Beta Thal Minor- Carrier / Trait, HBA2 > 3.5%, MCV<80”

256
Q

Hemoglobin C gene

A

HBB

257
Q

Hemoglobin C desc

A

Structural variant
“Hemoglobin C Disease: homozygotes -> hemoglobin C. Mild to moderate anemia.
Hemoglobin C beta thal disease. Mild to moderate anemia
Hemoglobin SC disease- form of sickle cell disease”

258
Q

Hemoglobin E gene

A

HBB

259
Q

Hemoglobin E desc

A

“Hemoglobin EE: homozygotes -> hemoglobin E. Low MCV, healthy.
Hemoglobin E beta thal disease: Blood transfusions, life long care. Most common severe form of beta thalassemia world wide
High variability.”

260
Q

Sickle Cell Disease gene

A

HBB

261
Q

Sickle Cell anemia variant

A

p.Glu6Val

Hb S trait in 1/10 african americans

262
Q

del(1)(p36)

A

Although the phenotype is variable, some of these patients have significant phenotypic overlap with Prader-Willi syndrome.

263
Q

dup(1)(q21.1)

A

Variable. DD, ASD, ADHD, schizophrenia, ToF.

264
Q

del(2)(q37.3)

A

Albright Hereditary Osteodystrophy.

265
Q

inv(2)(p11.2q13)

A

A recurring pericentric inversion. There appears to be no increased risk for liveborn unbalanced recombinant offspring among these inversion carriers although the risk for spontaneous abortions and stillbirths appears to be increased approximately 2-fold

266
Q

dup(3)(q26.3)

A

phenotypic overlap with Cornelia de Lange syndrome

267
Q

del(4)(p16.3)

A

A classic chromosome deletion syndrome. Wolf-Hirschhorn syndrome. Phenotype includes severe growth and mental retardation, microcephaly, “Greek Warrior helmet” face, cleft lip and/or palate. Although the critical region for the syndrome is in 4p16.3, deletions can be large or small. A milder phenotype associated with similar deletions is seen in patients with Pitt-Rogers-Danks syndrome.

268
Q

t(4;8)(p16;p23)

A

One of only 2 recurring constitutional reciprocal translocations; mediated by olfactory receptor gene clusters on chromosomes 4 and 8. Patients with unbalanced karyotypes and the der(4) have features associated with Wolf-Hirschhorn syndrome

269
Q

del(5)(p15)

A

A classic chromosome deletion syndrome. Cri-du-chat syndrome named for the characteristic high pitched cry in infants with 5p deletions that include the p15.31 and/or distal p15.2 region. Phenotype includes microcephaly, severe motor and mental retardation, round face, hypertelorism, micrognathia.

270
Q

del(5)(q35)

A

A classic chromosome deletion syndrome. The Sotos syndrome phenotype includes overgrowth, macrocephaly, mental retardation, hypotonia and poor coordination, advanced bone age and a typical facies (prominent forehead with recessed hairline, long narrow face, pointed chin, hypertelorism and large ears). Deletions are more common in the Japanese population (~ 50 of patients) than the non-Japanese (~10% of patients).

271
Q

del(7)(q11.2q11.2)

A

Williams syndrome. A true contiguous gene syndrome. Phenotype includes supravalvular aortic stenosis (SVAS), “elfin” face, mental and growth retardation, infantile hypercalcemia. Patients with Williams syndrome often have remarkable musical and verbal abilities. This is a submicroscopic deletion detectable by FISH. Genes within the deleted region thought to contribute to the phenotype include elastin (SVAS, aortic shenosis); LIM Kinase 1 (cognitive impairment); RFC 2 gene (reduced efficiency of DNA replication - growth and developmental delay).

272
Q

del(7)(q36)

A

Several patients have been reported with distal deletions in 7q and holoprosencephaly (type 3). 7q36 is the location of the sonic hedgehog gene.

273
Q

del(8)(q24.11-24.13)

A

Associated with the Langer-Giedion syndrome. This is probably a true contiguous syndrome with symptoms caused by disturbances of both the TRPS1 gene and EXT1. Phenotype includes mental retardation, microcephaly, multiple exostoses (growth on bone), redundant skin, and sparse hair.

274
Q

inv(8)(p23.1q22.1)

A

This pericentric inversion is typically seen in individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. These inversion carriers have an ~6% chance of having a child with recombinant 8 syndrome. The recombinant chromosome 8 contains a duplication of q arm material (q22.1qter) and a deletion of p arm material (p23.1pter). Children with this recombinant chromosome typically have MR, heart defects, seizures and a characteristic facies (hypertelorism, thin upper lip, anteverted nares, wide face, abnormal hair whorl, low set ears, downturned mouth, low posterior hairline, etc).

275
Q

Trisomy 8.

A

Although full trisomy 8 is often lethal, many patients have been reported with mosaic trisomy 8. The phenotype includes a variable degree of MR (mild to moderate) with a tendency to poor coordination, prominent forehead, deep set eyes, strabismus, hypertelorism, cleft palate, joint contructures and other skeletal abnormalities, deep creases on palms and soles.

276
Q

t(8;14)(q24;q32)

A

present in 75-85% of Burkitt’s lymphoma cases

277
Q

del(9)(p24)

A

Partial monosomy 9p is associated with male to female sex reversal suggesting the presence of a gene important for normal male development. Patients with 9p deletions also have MR, motor development delay, trigonocephaly, wide nasal bridge, long fingers and toes, etc.

278
Q

inv(9)(p11q13)

A

A recurring pericentric inversion that is not associated with an increased risk for liveborn unbalanced recombinant offspring, spontaneous abortions or stillbirths.

279
Q

Trisomy 9 mosaicism.

A

Phenotype includes severe MR, and growth deficiency, sloping forehead, deeply set eyes, joint contractures, and heart defects.

280
Q

t(9;22)(q34.1;q11.2)

A

Philadelphia chromosome. 90% of patients with chronic myeloid leukemia (CML) have the Philadelphia chromosome

281
Q

del(10)(p13-14)

A

A small number of patients with the DiGeorge phenotype have been reported with deletions of 10p.

282
Q

dup(11)(p15.5)

A

Patients with duplications in this region of 11p have been reported with Beckwith-Wiedemann syndrome. The primary features associated with this syndrome include macroglossia (enlarged tongue), omphalocele (protrusion of abdominal contents through umbilicus, macrosomia (gigantism) and ear creases.

283
Q

del(11)(p13)

A

Interstitial deletions of 11p13 are associated with WAGR (Wilms tumor; aniridia-genitourinary anomalies-mental retardation syndrome). This is a true contiguous gene syndrome with separate genes responsible for aniridia (AN2) and Wilms tumor and genitourinary anomalies (WTI).

284
Q

del(11)(p11.2)

A

Potocki-Shaffer syndrome is a newly recognized deletion syndrome. These patients typically have multiple exostoses, an enlarged parietal foramina, craniofacial dysostosis and MR.

285
Q

del(11)(q23)

A

Deletions including 11q23 are associated with Jacobson syndrome. Phenotype includes growth and psychomotor delay, trigonocephaly, strabismus, telecanthus, camptodactyly, thrombocytopenia. This deletion may be caused by an inherited fragile site at 11q23.3 in some patients.

286
Q

“plus”i(12)(p10)

A

Tetrasomy 12p secondary to an extra isochromosome of 12 short arm is associated with Pallister-Killian syndrome. This syndrome is an example of tissue limited mosaicism. The isochromosome 12p is typically found in fibroblasts, but not in the lymphocytes. Phenotype includes profound MR, seizures, streaky pigmentation, sparse hair (especially in temporal areas), coarse facial features in older patients.

287
Q

del(13)(q14.2)

A

Deletions of 13q that overlap this region are associated with a high risk of developing retinoblastoma (tumor of the retina).

288
Q

del(15)(q11-13)pat

A

Prader Willi
Paternal deletion: ~75%
mat UPD: 25%
Paternal imprinting defect: ~1%
Lack activity of paternal genes MKRN3, MAGEL2, NDN, SNURF-SNRPN, and several snoRNA genes (as well as overexpression of maternal genes UBE3A and ATP10C) in 15q11q13
UPD usually nondisjunction in maternal meiosis I (associated with AMA)
Hypotonia, failure to thrive, DD/ID, obesity, short stature, hypogonadism, behavior problems, small hands and feet, hypopigmentation.

289
Q

del(15)(q11-13)mat

A

Angelman
Maternal deletions : 65-75%
Maternal UBE3A mutations: 5-11%
Paternal UPD: 3-7%
Maternal imprinting defects: 3%
Unknown: 15-20%
Lack the activity of the maternally expressed UBE3A (and ATP10C) genes in 15q11q13
Imprinted UBE3A expression restricted to brain cells (normal).
Typically isodisomic (postzygotic monosomy rescue, associated with null ovum and AMA) or more rarely paternal meiosis II errors
ID, absent speech, ataxia, hypertonia after infancy, microcephaly, seizures, happy/laughing disposition

290
Q

“plus” inv dup(15) or psu idic(15)(q)

A

These small, often dicentric chromosomes are composed of 2 copies of chromosome 15 short arm, (usually) 2 centromeres and 2 copies of varying amounts of proximal 15q material. If the “marker” contains the probe loci that are usually deleted in PWS/AS, the patient will have MR and often autism. If these loci are not present in the marker, the phenotype can be normal. These are the most common identifiable markers or ESAC’s seen in the human population.

291
Q

t(15;17)(q22;q11-21)

A

Acute Promyelocytic leukemia (APL) (form of AML). Pathognomonic

292
Q

del(16)(p13.3)

A

alpha-thalassemia/MR syndrome. Patients with small deletions in 16p have been observed with alpha thalassemia, MR, and a broad spectrum of associated anomalies.

293
Q

del(16)(p13.3)

A

Rubinstein-Taybi syndrome can also be associated with deletions in this region. Phenotype includes broad thumbs and great toes, mental retardation, small mouth, beaked nose, micrognathia, low hair line, heart defects, skeletal abnormalities.

294
Q

dup(16)(p11.2)

A

Microcephaly, DD, ID, ADHD

295
Q

del(17)(p13.3)

A

Miller-Dieker syndrome; 90% of patients with MDS have either a visible or submicroscopic deletion in this region. Phenotype: microcephaly, with lissencephaly (smooth brain). Also unusual facial appearance, and malformations of the heart and kidneys, polydactyly.

296
Q

del(17)(p11.2)

A

Visible deletions in this region are associated with Smith-Magenis syndrome. Phenotype includes brachycephaly, midface hypoplasia, prognathism, hoarse voice, MR, growth retardation, behavior problems (including self-destructive behavior and sleep disturbances). More distally placed deletions within the 17p11.2 band are associated with HNPP.

297
Q

dup(17)(p11.2)

A

Several patients have now been reported with visible duplication of the same region deleted in Smith-Magenis syndrome. These patients had developmental delay without distinctive physical features.

298
Q

del(17)(p11.2)

A

(Generally submicroscopic) Deletion of the same region duplicated in CMTIA is associated with Hereditary Neuropathy with liability to Pressure Palsies (HNPP). More proximally placed deletions involving the 17p11.2 band are associated with Smith Magenis syndrome

299
Q

dup(17)(p11.2)

A

(Generally submicroscopic) duplications of this region are associated with Charcot-Marie Tooth disease (CMTIA), a peripheral neuropathy associated with muscle weakness. Deletions of this region are associated with HNPP

300
Q

18p deletion

A

Deletion of all or a large portion of 18p is a classic chromosome deletion syndrome. The associated phenotype includes moderate growth deficiency, MR, hypotonia, microcephaly, holoprosencephaly, micrognathia, large ears.

301
Q

18q deletion

A

classic chromosome deletion syndrome. These are relatively large deletions, some interstitial, some apparently terminal. The phenotype includes MR, short stature, hypotonia, hearing impairment and foot deformities.

302
Q

del(20)(p12.3)

A

del(20)(p12.3) Deletions in this region are associated with Alagille syndrome, although fewer than 7% of individuals with Alagille have visible deletions. Alagille syndrome is caused by mutations of JAG1. Phenotype includes paucity of intrahepatic bile ducts, posterior embryotoxin (visible ring in the cornea) and other anomalies.

303
Q

del(22)(q11.2)

A

This small deletion in proximal 22 is associated with DiGeorge/VCF (velocardiofacial AKA Shprintzen syndrome. DiGeorge syndrome is the infantile presentation including neonatal hypocalcemia, susceptibility to infection, and conotruncal heart anomalies. In older children, VCF syndrome includes bulbous nose with square nasal tip, hypernasal speech with (generally) milder cardiac anomalies. Short stature and mild-to-moderate learning disabilities are often seen, as well as psychiatric disorders in adults. The acronym CATCH 22 [cardiac abnormality, abnormal facies, T-cell deficit due to thymic hypoplasia, cleft palate, hypocalcemia, resulting from del(22)(q11)] has been proposed to describe the variable phenotype. Although the majority are de novo, approximately 10% are inherited deletions from an affected (often mildly affected) parent.

304
Q

“plus”idic(22)(q11.2)

A

Cat eye syndrome. An extra small marker chromosome is present representing tetrasomy (or occasionally trisomy) of 22q11.2. Phenotype includes mild mental retardation, coloboma of the iris, downslanting palpebral fissures, preauricular tags or pits, and anal atresia.

305
Q

del (22)(q13)

A

Phelan-McDermid syndrome. Infantile hypotonia, normal growth, profound developmental delay, absent or delayed speech, and dysmorphic features. Decreased pain sensitivity. Decreased sweating. Cyclic vomiting.

306
Q

del(X)(p22.3p22.3)

A

Males have X-linked ichthyosis.

307
Q

del(X)(p22.3p22.3)

A

Males with Kallmann syndrome typically carry a submicroscopic deletion involving the Kallmann syndrome 1 (KAL1) gene and demonstrate hypogonadotropic hypogonadism and anosmia (inability to smell). Carrier females typically have milder manifestations.

308
Q

dup(X)(p22p22)

A

PLP PROTEOLIPID PROTEIN 1; Pelizaeus-Merzbacher disease is a dismyelinating disorder of the CNS; clinical signs include nystagmus, spastic quadriplegia, ataxia and developmental delay.

309
Q

dup(X)(p21p21)

A

Sex-reversed XY males result from duplication of the DAX1 gene. In the presence of a DAX1 duplication, the male determining function of SRY is suppressed and ovarian development results.

310
Q

inv(Y)(p11;q11)

A

This pericentric inversion typically represents a benign variant, however some inversions have been reported in males with infertility due to a small accompanying deletion.

311
Q

UPD 6 pat

A 
Transient neonatal diabetes mellitus
~33% of cases
"~33% maternal hypomethylation
~33% paternal duplication
Overexpression of the imprinted loci PLAGL1 and HYMAI in 6q. Macroglossia, other congenital anomalies
312
Q

UPD 7 mat

A

Russell-Silver syndrome
~7-10% of cases
Loss of paternal methylation at IC1: 35-50%
Unknown: 40%
Maternal duplication of IC1 and IC2: 1-2%
Hypermethylation of the imprinting center of the MEST gene in 7q
Prenatal and postnatal poor growth, relative macrocephaly, hemihypoplasia

313
Q

UPD 11 mat

A 
Russell-Silver syndrome
Rare, <10 known cases
Hypomethylation of IC1 in 11p
Biallelic expression of H19
Silencing of IGF2
Postzygotic origin
314
Q

UPD 11 pat

A

Beckwith–Wiedemann syndrome
~20% of cases
Loss of maternal methylation at IC2: 50%
Unknown: 20%
Gain of maternal methylation at IC1: 5%
Maternal CDKN1C mutations: 5%
Other chrm. abnormalities: 1%
Abnormalities within two differentially methylated regions 11p: imprinting center 1 (IC1), which regulates the expression of H19 and IGF2, and imprinting center 2 (IC2), which regulates the expression of CDKN1C, KCNQ1, and KCNQ10T1.
Arises from postzygotic somatic recombination (hypothesis that whole UPD11 is lethal)
IGF2 is a fetal growth factor (biallelic expression responsible for overgrowth)
Congenital overgrowth, predisposition to tumorigenesis, hemihyperplasia

315
Q

UPD 14 mat

A

Temple syndrome
Loss of expression of all paternally expressed genes (DLK1, RTL1, and DIO3) and overexpression of maternally expressed genes (noncoding
RNAs, miRNAs, and snoRNAs) at 14q
Most common cause of TS
Prenatal and postnatal poor growth, mild DD, hypotonia, hypermobility, small hands and feet, truncal obesity, precocious puberty, short stature

316
Q

UPD 14 pat

A

Kagami–Ogata syndrome
Severe phenotype with polyhydramnios, large omphalocele, thoracic dysplasia (coat-hanger sign on X-rays = pathognomonic), with respiratory failure, abdominal wall defects, poor growth, developmental delay, and facial abnormalities

317
Q

McCune-Albright syndrome

A

Not inherited. Sporadic and mosaic throughout body (GNAS mutation)
polyostotic fibrous dysplasia, precocious female puberty, coast of Maine skin findings, various endocrine problems

318
Q

Achondrogenesis inher

A

“Type 1: AR

Type 2: AD; ~100% de novo”

319
Q

Achondrogenesis desc

A

“Severe. Small body, short limbs, other skeletal anomalies.

Often stillborn or die in infancy”

320
Q

Chromosome instability syndromes

A

Fanconi, AT, Bloom

321
Q

Microarray is first tier test for

A

ID, DD, autism, and multiple congenital anomalies

322
Q

~X% of pt with normal CMA and abnormal phenotype have a balanced rearrangement on karyotype

A

1%

323
Q

When is karyotype warranted after microarray?

A

Karyotype for complex rearrangements indicated when multiple CNVs identified on array

324
Q

Ethics of recontacting

A

Attempt to recontact if new info that could impact care is available (based on beneficence)
Discuss recontact plan at initial results
Shared responsibility of lab, provider, and pt

325
Q

Imprinting chromosomes

A

6, 7, 11, 14, 15, 20, (x)

326
Q

Nondisjunction in meiosis I can result in (upd)

A

heterodisomy

327
Q

Nondisjunction in meiosis II can result in (upd)

A

isodisomy

328
Q

How do you distinguish between UPD vs abnormal methylation?

A

Satellite marker analysis

329
Q

1/x live births has a chromosomal abnormality

A

150

330
Q

With low fetal fraction (drawn at appropriate date) offer

A

diagnostic testing, not repeat NIPS

331
Q

Criteria for conditions that should be included in gen pop carrier screening

A

Most at risk couples would consider prenatal dx for this condition

332
Q

All planning or pregnant women should be offered screening for

A

SMA, CF, and a CBC for anemia and hemoglobinopathies

333
Q

genome editing statement

A

Embryos should not have gene editing at this time

334
Q

Pathogenic variants in X genes should be reported as X findings if encountered on WES/WGS

A

59, secondary

335
Q

Active engagement in WES/WGS consent starting around age X, depending on maturity of child

A

8

336
Q

CHD 22q

A

ToF>IAA and VSD

337
Q

CHD CHARGE

A

Conotruncal defects

AV canal defects, aortic arch anomalies

338
Q

CHD Alagille

A

Pulmonary artery stenosis, VSD, ToF

339
Q

CHD Noonan

A

Pulmonic stenosis, HCM

340
Q

CHD Williams

A

Supravalvar aortic stenosis

pulmonic stenosis, coarctation of aorta

341
Q

CHD Turner

A

Coarctation of the aorta

bicuspid aortic valve, ASD, VSD, hypoplastic left heart, regurgitation, aortic aneurysm and dissection

342
Q

CHD with Increased Pulmonary Flow

A

VSD, ASD, AVSD, PDA

343
Q

CHD with Cyanosis / Left to Right Shunt

A

Transposition of Great Arteries, Persistent Truncus Arteriosus, Tetralogy of Fallot, Tricuspid Atresia, Pulmonary Atresia, Ebstein Anomaly

344
Q

Pulmonary stenosis

A

Pulmonary valve is too small, narrow, or stiff

345
Q

Persistent Truncus Arteriosus

A

Single blood vessel (truncus arteriosus) comes out of the right and left ventricles, instead of the normal 2 vessels (pulmonary artery and aorta)

346
Q

Tetralogy of Fallot

A

VSD, overriding aorta (aorta shifted to above VSD, so gets blood from both ventricles), pulmonary stenosis, right ventricular hypertrophy

347
Q

Ebstein Anomaly

A

Tricuspid valve (between right ventricle and atrium) malformed

348
Q

Most common cause of BWS

A

Loss of maternal methylation at IC2 (50%)

349
Q

Thrombophilias

A

Factor V Leiden, prothrombin thrombophilia, protein s deficiency, protein c deficiency

350
Q

estrogen containing birth control contraindicated for

A

Factor V Leiden homozygotes (or hets with VTE Hx)

351
Q

HbF

A

2 alpha, 2 gamma

352
Q

HbA2

A

2 alpha, 2 delta

353
Q

HbH

A

beta tetramer

354
Q

HbBarts

A

gamma tetramer

355
Q

MCV with hemoglobin Bart hydrops

A

high!

356
Q

Hb Constant Spring

A

Nucleotide change in stop codon of HBA2, resulting in 31 extra aa

357
Q

SMN2

A

Pseudogene of SMN1. Has single nucleotide difference that causes 85% of transcripts to skip exon 7, making that 85% nonfunctional

358
Q

Type 4 CMT inher

A

AR (1 and 2 are AD)

359
Q

LGMD Type 1

A

AD

360
Q

LGMD Type 2

A

AR

361
Q

Autism spectrum frequency

A

1/60 children

362
Q

cma yield for asd

A

5-15% yield

363
Q

Recurrence risk for idiopathic ASD in a sibling

A

up to 20% (ACMG has 4-7%)

364
Q

No invasive procedures (eg c’spy) for this condition

A

Vascular EDS

365
Q

Cleft Lip +/- cleft palate: between X-X% will have additional “problems” (additional defects, chromosome abnormalities)

A

7-35%

366
Q

Cleft palate only: X% isolated

A

50%

367
Q

NTD/AWD serum screening

A

AFP > 2.5 Mom

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