Cardiac Genetics (M/A)

Cardiac Genetics MA26

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

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