Genetic Testing
-Chromosomal Analysis
-Karyotype - Initially could see gross changes, like change in chrom #- Tri 21,
-Banding techniques then came about to see smaller visible deletions or duplications - Giemsa staning
-FISH - Fluorescence in situ hybridization & MLPA - Multiplex Ligation-Dependent Probe Amplification & Microarray techniques- can detect smaller del or duplications
-Microarrays have allowed ID of many more deletions and duplications, and is now the test of choice for many pts and centers bc it can survey the entire genome
-Linkage Analysis- to ID gene responsible: if many pts in family have the dz, can use LA to map the dz gene to a particular chrom position- used for Marfan, Holt Oram, and Noonans, and familial ASD + AV conduction block etc.
-CMA has led to ID more prev unrecognized submicroscopic del/dup, so are defining new genetic syndromes
-Whole Exome Sequencing is going to do the same...
-Many CHD are more complex, from a combo of genetic and env factors, and many genes to cause the same lesion
-Common or rare variants- unknown how much single nucleotide polymorphism (SNPs), deletions, or duplications contribute to the dz
Patterns of Inheritance & Familial Risks
-2-4% of recurrence for any CHD in a person w a parent or sibling affected
-recurrence risk increased if >1 sibling is affected
-?if affected mom worse than affected dad
-L sided lesions- one study had 8-19% risk of recurrence if first degree relative is affected, espec if it was HLHS (19%) and CoAo (9%). Less w TGA (2.4%).
Genetic Syndromes
Syndromes Associated with Chromosome Abnormalities
-In general population, 13% had a chrom abNly detected by 1yo ???really?
-and in 19-36% of miscarriages/stillborns w a heart defect
-Aneuploidy - an increase or decrease # of a whole chromosome
-Duplication or Deletion, Partial Trisomy, Partial Monosomy - incr or decr in part of a chrom.
-CMA can dx a causal Dx in up to 18% of 'syndromic CHD'
Aneuploidies
Down Syndrome
-Trisomy 21 in 94%, remainder w partial tri of chr21 bc of a translocation or mosaicism
-Facial AbNlies - varies by age and range
-Hypotonia, dev delay, mod intellectual disability, microbrachycephaly, small ears, mouth, and nose, protruding tongue, upslanting eyes w epicanthal folds, transverse palmar creases, sparse hair
-Skeletal anom- 5th finger clinodactyly, brachydactyly, gap bn 1st/2nd toes, atlantoaxial instability, hypoplastic pelvis, joint laxity
-Vision, Hearing, Endocine, Heme, Reproductive, and GI xx too
- ~1/2 have a CHD, of which 40% has an AVSD (up to 60% if include primum defects)
-3/4 of pts w AVSD have Tri21
- Other CHD- 2nd ASD, PM/M VSD, TOF, PDA w hemodynamic significance
- R/F - mom >35yo has incr risk of aneuploidy; less freq in nonHispanic blacks
- Median age at death - now 49yo in 1997 vs just 25yo in 1983
- Mosaic pts have similar rate of CHD 42% vs 50% - ASD was #1 and AVSD seen in 11%
- Some suggest it is Chr 21q22 region that --> AVSD
- Post repair, should assess for conduction block w variable escape, w periodic Holters
Trisomy 18
-Most do not survive through birth
-Short palpebral fissures, small mouth, micrognathia, growth retardation, prominent occiput, clenched hands, disorganized/hypoplastic palmar creases, hyperconvex nails, short sternum, small nipples, radial defic, and xx to ~every organ
-CHD- ~ubiquitous - PM VSD, TOF, DORV, polyvalvar dz w thick, myxomatous or dysplastic leaflets
-NHx- prevalence (UK study) 1/4000 pregnancies at 18 wks, --> 1/8000 births;
-91% die by 1yo, although CHD doesnt affect survival
-All w severe MR
-Some parents adavocate for CV and other surgeries
Turner Syndrome
-1/2000 prevalence
-1/2 w 45,XO, or has a structurally abNl X chrom
-Most common presentation: spont abort w fetal hydrops or lymphatic malformn in neck/mediast
-Fetal lymphedema--> neck webbing, protrude ears, low hairline, puffy hands/feet, deep set nails
-Short 4th metacarpals, cubitus valgus, Madelung deformity, osteoporosis, kyphoscoliosis, broad chest w wide spaced nipples, renal anom (horseshoe kidney), nevi, hearing loss, infertile, A/i dz, deficit in visual-spatial/preceptual ability, attn, and social skills
-XO pts have more xx than pts w partial del of an X
-Mosaicism- 45X/46XX is usually milder
- 45X/46XY has incr risk of gonadoblastoma
-30% pts have CHD - usually L heart xx
-up to 1/2 of adults have vasc anom seen on MRI
-ASx bicuspid Ao in 15%, and 10% can progress to AS
-CoAo in 10% pts
-CHD is much assoc w neck webbing, so maybe it's the altered lymphatic drainage that --> L heart obst lesions
-other L side xx- elongation of Tx Ao, or pseudoCoAo (seen in ~1/2 pts w Turners), MV anom (<5%), and HLHS (rare).
-2nd ASD, PM VSD, pAPVR involving LUPV, and LSVC seen too
-complex CHDs (espec conotruncal xx) are rare
-incr risk of Ao dilation, dissection, and sudden death
-check MRI in older pts bc it doubles the rate of detection of Ao dil'n (33% vs 16% by echo)
-recheck MRI q5-10 yrs, or if pt has htn, or pt wants to get pregnant.
-likely more diffuse vasculopathy bc of incr risk of cerebral vasc xx
-Ao dissection is near always assoc w another Ao xx- bicuspid Ao, CoAo, htn
-Growth Hormone doesnt affect Ao diln
-Pregnancy puts pt at higher risk of Ao diln
-Must monitor for recarc and htn postop, AS and AR
-Unrepaired bicusp Ao vlv = monitor for dvpt of AS and Ao diln
-Htn and cor art dz are at incr risk in Turner
-Check ECG for conduction and repol xx (long QT)
Deletion-Duplication Syndromes
22q11.2 Deletion Spectrum - DiGeorge Syndrome, Velocardiofacial Syndrome
-1/6000 life births
-very variable phenotype
-6-10% are familial- inherited chrom deletion fr a parent
-often don't dx parent's carrier state until after child is dx'd
-CHD, palate xx, feeding xx, speech & LD xx, hypOCa, Immdefic, Renal xx, Behavioral and Psych xx, facial features... (hard to dx facial xx in Afr Americans)
-CHD in 75-80% of pts
-TOF, Interr Ao Arch Type B, Trunc Art
-PMVSD, Ao Arch xx, P Vlv stenosis, ASD, heterotaxy, HLHS too
-1/2 of pts w Inter Ao Arch B, 35% of Truncus, 24% of pts w isolated Ao Arch anom, and 15% of TOF, and 110% of PM VSD have 22q11 del.
- <1% of DORV and d-TGA have 22q11 del,
- if they have any of above + an Arc xx too (abNl sidedness, cervical arch, abNl branching) then more likely to have 22q11 del
-if TOF/APV or AP collat have higher risk
-All pts w Inter Ao Arch B, Truncus, TOF, Isolated Arch anom should be tested for 22q11 del
-some also rec testing pts w PM VSD + Arch xx
-Parents w 22q11 del have a 50% chance of transmitting the chrom in subsequent pregnancies
-Eval pts for low Ca, imm defic, Palate xx, feeding and speech d/o, renal and skel xx, cognitive xx, behavioral xx
-in pts w asthma sx, c/s a vascular ring instead...
-Dx w FISH, MLPA, or CMA
7q11 Deletion - Williams-Beuren Syndrome
-aka Williams Syndrome
-1/20,000 births
--> CHD: 55-85% pts have CHD
-supravalvar AS &/or supravalvar PS
-the AS can --> LVH/LV fail, sudden death is a known complication- 7/10 sudden deaths were fr cor art stenosis + severe biventric OTO &/or arrhythmiaa
-hypertension - renal art stenosis or ideopathic
-must follow lifelong bc of the htn risk and diffuse arteriopathy
--> hypErCa (15% pts)- as an infant, resolves w time,
--> skeletal xx
--> renal xx
--> cognitive xx - mild MR (but ranges fr sev to Nl)
-good auditory rote memory; poor visuospatial construction tasks
--> social personality- overly friendly, but also has much behavioral disorders- inattention, hyperactivity
--> elfin facies
--> broad range of Sx (see ref 206)
-90% of clinical WIlliams is bc of 7q11.23del- not seen by karyotype, but +seen on FISH, MLPA, or CMA
-bc the Sx are varied, c/s genetic testing in any pt w supravalvar AS or PS
-Genes: ELN = elastin gene, and others in this region
-xx to ELN has been seen in pts w isolated supravalvar AS without Williams
-other genes: LIMK1 seen in impaired visiospatial construction cognition
-7q11.23 del--> complete loss of one copy of ELN --> the diffuse arteriopathy
-disruption/mutation of ELN alone can --> the rare, isolated supravalvar AS/PS
-ELN mutation--> auto dom form of cutis laxa- loose, sggy, inelastic skin; the elastin fx is diff fr that of diffuse arteriopathy seen w William's, acting as a dominant negative effect (producing a bad prtn that interferes w stuff, rather than just the lack of protein formation)
Emerging Microdeletion/Microduplication Syndromes
-much variability at SNP (single nucleotides) and large segments of DNA (copy number variants)
-nearly 20% (depending on Sn of the study) have a unique/rare copy number variants
11q23 Deletion Syndrome = Jacobsen Syndrome
-facial features- widely spaced eyes, mild ptosis, small ears
-thrombocytopenia
-dev delay
-CHD - 56% of pts - 1/3 were VSD, 1/3 were L heart xx (MV/Ao vlv)
-short
-GU xx
-pyloric stenosis
-ophthalmologic xx
-very variable phenotype
8p23.1 Deletion Syndrome
-growth impairment
-dev delay
-behavioral problems
-microcephaly
-diaph hernia
-hypospadia
-CHD (see ref 47-48)
-AVSD, ASD, VSD, pulm vlv stenosis
-GATA4 gene often xx, though there are pts w GATA4 deletion w/o CHD, and those without GATA4 del with CHD
1p36 Deletion Syndrome
-#2 most common deletion syndrome
-1/5000 to 1/10000 live births
-facial xx
-ocular xx/vision problems in 52%
-hearing loss in 47%
-neuro xx
-skeletal xx 41%
-renal xx 22%
-CHD in 71% - ASD, VSD, PDA, valve xx, TOF, CoAo, and many w CM - LVNC or DCM
Genetic Syndromes Caused by Mutations in Single Genes
-inherited in mendelian fashion
-variable phenotype... so additional genetic/env factors may come into play
-diff mutations can cause similar Sx/phenotype = genetic heterogeneity
-see GeneReviews.org for peer reviewed sources...
Alagille Syndrome - JAG1 & NOTCH2
-paucity of bile ducts in liver
-cholestasis
-CHD
-R sided CHD - periph PS (diffuse hypoplasia of pulm art bed, or discrete stenosis)
-Pulm vlv stenosis
-TOF
-some pts do have L sided lesions
-there are some pts w CHDs w JAG1 xx w/o hepatic xx
-c/s Alagille synd or JAG1 xx in families w >1 person w R heart xx
-and check for other R heart xx in any pt w a right heart lesion
-skeletal xx
-ocular xx
-facial features
-additional vasc xx
-arteriopathy of non pulm vasc bed
-one study showed 9% of Alagille pts w noncardiac vasc xx - basilar, internal carotid, middle cerebr art aneurysms; renal art stenosis, moyamoya dz
-in these pts, 34% of the dead died from a vascular event
-? true prevalence or whether screening is appropriate
-Auto Dom - deletion at 20p12 in some pts
-Notch ligand JAG1 is in the deleted region
-5% have del of of one JAG1 gene copy, but most pts have various intragenic JAG1 mutations
-JAG1 mutation seen in 94% of pts
-can be a missense or a frameshift mutation (most common cause)
-dz mech is one of haploinsufficiency - there is 1/2 the amt of fxl protein
-Some pts have NOTCH2 mutations - NOTCH2 is the ligand for JAG1
-all these pts had renal xx, more than that of JAG1 pts
-if one suspects pt of having Alagille synd, then get karyotype to check for 20p12 del or for JAG1 in particular...
Holt-Oram Syndrome - TBX5
-1/100,000 live births
-Auto dom for skeletal xx w full penetrance of the preaxial radial ray xx
-might have only subclinical signs w abNl carpal bn on CXR, others have sev xx w phocomelia (malformed limb...)
-thumb frequently affected- triphalangeal, hypoplastic, or absent
-can be uni or bilateral, symmetric or asymmetric
-75% of pts w HOS have CHD
-ASD in 58%, VSD in 28%; also AVSD, conotruncal, L sided xx seen
-AV conduction delay- ranges from 1st to complete HB
-by linkage analysis - see Auto Dom mutation at 12q24, then TBX5 gene was ID'd
-TBX5 mutation seen in 70% of pts w HOS Sx- can be nonsense, frameshift, missense mutn
-c/s in any pt w an upper limb xx and any heart problem
Noonan Syndrome Spectrum
- Noonan Syndrome - LEOPARD - Cardiofaciocutaneous Syndrome - Costello Syndrome
-Similar Sx, diff genetics
-aka Ras/MAPK (mitogen-activated protein kinase) pathawy aka rasopathies
-Cardiac xx - CHD, HCM, arrhythmia
-also see NF1 & Legius syndrome
Noonan Syndrome
-1/1000 to 1/2500 live births
-abNl facies- ptosis, hypertelorism, lowset ears, low posterior hairline
-webbed neck
-pectus excavatum
-bleeding diathesis
-lymphatic xx
-learning xx
-variable intellectual disability
-cryptorchidism
-Genetics: PTPN11, SOS1, KRAS, RAF1, NRAS, BRAF, SHOC2
-PTPN11 encodes a tyrosine phosphatase SHP-2, which fx's in the ras/MAPK pathway. 1/2 of Noonan's has this
-80% of Noonan's has a cardiac xx
-60% of which are CHD, 20% HCM
-P vlv stenosis, often w ASD in 25-35% (#1 xx)
-also: ASD, VS, TOF, PA stenosis, CoAo, primum ASD, polyvalvulopathy
-HCM in 20% of pts w Noonan- espec if RAF1 xx, rare w PTPN11 xx
-KRAS xx --> worst Sx
-SOS1 xx --> less chance of cog xx
-SHOC2 xx --> more likely to have MVP, ASD/VSD, growth hormone defic, hyperactive behavior, hypernasal speech, easily pluckable hair
-Most Noonan's is sporadic, but some have an Auto Dom inheritance
-much variability, some parents were dx'd after kids...
-PTPN11 xx - seen in other syndromes that overlap w Noonan
-Noonan-like/Multiple Giant Cell Lesion Syndrome - Noonan sx + giant cells of bone/soft tissue
-LEOPARD syndrome - Auto Dom- multiple lentigines (small pigmented skin spots), ECG conduction abNlies, ocular hypertelorism, pulm vlv stenosis, HCM, growth retardation, abNl genitalia, SN deaf
-but LEOPARD is genetically heterogeneous, so might not have PTPN11 xx
-CFC Syndrome & Costello - can DDx fr Noonans as older child, but very similar at fetus/infant/toddler
-CFC Syndrome- BRAF, MEK1, MEK2 xx
-also have macrocephaly, hypertelorism, ptosis, but w coarser facial features- sparse eyebrows/eyelashes, dry skin
-Costello Syndrome- HRAS xx
-also has coarse facial features, ulnar deviation of the hand, curly or very straight hair, hyperpigmntn, loose skin, deep palmar and plantar creases, papillomata, premature aging
-Posteror fossa crowding --> Chiari 1 malformation, hydroceph, syrinx
-all have dev delay, moderate MR
-10-15% risk of neoplasia- espec rhabdo
-all 3 have an 80% CV xx rate, w HCM more common in Costello and LEOPARD (60% of dz)
-atrial tachy, espec multifocal atrial tachy, seen most in Costello
Kabuki Syndrome - MLL2
-expressionless facial appearance
-elongated palpebral fissrues w everted lower lids, earched eyebrows, sparse lateral brows, large pinnae, fetal finger pads
-renal xx
-digit xx
-immune xx
-feeding xx
-intellectual delay
-much phenotypic variability
-CHD- ASD, VSD #1, also L sided CHD w HLHS/Shone's variant
CHARGE Syndrome - CHD7
-1/10,000 to 1/15000 live births
-CHD7 xx on chrom 8q12.1 in 65% of pts w CHARGE
-Coloboma (retina or choroid) + CHD + Choanal Atresia + Retardation pf postantal growth and dvpnt (& low tone), brain anomalies, GU xx (e.g. hypogonaotropic hypogonadism), external ear xx (small, square, cupped pinnae) and/or deafness (conduction, SN or both)
-also can have cranial n weakness/palsy w facial asymm, hypoplasia of chochlea or semicircular canals
-Oral clefts and neurogenic swallowing xx also seen
-may have some features of autism, but might be bc of visual and auditory xx
-CHD
-92% of pts w CHD7 xx have CHD, and 71% of pts w/o it have CHD
-conotruncal and Ao Arch xx
-DiGeorge phenotype have been seen in some pts
Heterotaxy Syndromes
-neither a typical genetic syndrome, or isolated CHD
-due to xx of right-left axis determination (see ref 129)
-1/10,000 birth prevalence
-= laterality of thoracoabd viscera is neither usual or inverted (but rather is mixed)
-See cardiac, pulm, renal, GI, and minor systemic vn xx (e.g. interr IVC), along with midline xx of brain and face
-R/F- IDM, but also some chrom xx
-Kartagener ysndrome genese bing IDd... auto rec, w some auto dom or x-link rec inheritance
-genetic heterogeneity w axonemal dynein intermediate chain on chrom 9p21 and also on 7p and 5p
-...
VATER/VATERR/VACTERL Association
-? cause
-rarely seen in tri 18 or tri 21 pts
-Vertebral xx, Anal atresia +/- fistula, TEF, REnal dysplasia, then add radial xxx or thumb hypoplasia/absence, preaxial polydactyly
-Then, added CHDs, single umbilical art, lower spine anom
-CHDs: varied
-if assoc w hydroceph, it is assoc w FHx of hydroceph, and is likely mendelian w auto dom/rec/xlink inheritance, but remainder are sporadic
Hemifacial Micrsomia, Facioauriculovertebral Spectrum, & Oculoauriculovertebral Spectrum, Goldenhar Syndrome
-xx of the 1st & 2nd branchial arches is complex
-eye, mandibular, ear, nearve, soft tissue xx too
-unilateral xx w variable hypoplasia of facial structures - bn, soft tissue, ear, eye, mouth
-ear tags/pits, epibulbar dermoids (seen w Goldenhar syndrome) and deafness
-oral clefts- lip, palate, mouth corner --> macrostomia
-assoc w vertebral, radial, rib xx
-renal xx
-midline brain xx- agenesis of corpus callosum, encephalocele, lipma
-much overlap bn each
-CHDs
-in about 1/3 of pts on the spectrum but a very broad range is reported
-2/3 of CHD is TOF and VSD
Genetics of Isolated Congen Heart Defects - NKX2.5, GATA4, NOTCH1
-genetic basis for isolated, nonsyndromic CHDs is ill defined
-NKX2.5 and GATA4 are transcription factors, and NOTCH1 "regulates cell fate"
NKX2.5
-ASD and AV conduction xx seen w it
-chrom5q
-critical for AV nd dvp and fx
GATA4
-ASDs seen in some kindred
-variety of ASD, VSD, pulm vlv stenosis seen in other kindred
-chrom 8p22-p23.1, a 'molecular partner w NKx2.5'
-deleted when pt has an 8p23 del
NOTCH1
-seen in 2 families w bicupsid Ao vlv and Ao vlv stenosis
-plays a role in Ao vlv Ca'ion
-sporadic cases of L heart xx- Ao vlv stenosis, bicupsid AO, CoAo, HLHS
Genetics of Specific Lesions
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