HG400A Conditions

Huntingtons Disease (HD)

NEURO

HTT

• anticipation/sex-specific anticipation (worse when passed from dad)

• trinucleotide repeat disorder - CAG repeats

• Symptoms: chorea, muscle rigidity, slowness (mentally and physically), poor gait, mental health issues

Marfans

CARDIO/GENERAL

FBN1

• AD

• Symptoms: dilated aorta, long spindly limbs, “thumb sign”, lens dislocation

Duchenne Muscular Dystrophy (DMD)

PEDS

DMD

• X-linked recessive

• Symptoms: muscle degeneration and weakness, specifically in claves

  • pts stand up a certain way due to weakness in back of legs

DiGeorge Syndrome

PEDS

22q11.2 deletion (ex. of interstitial deletion)

*mostly de novo, but 10% are passed from an affected parent (~15-18% recurrence risk)

*lower occurrence in African heritage

• Symptoms: conotruncal heart defects, hypocalcemia (low calcium) d/t hypoparathyroidism, immune deficiency d/t thymic aplasia/hypoplasia, craniofacial dysmorphia, cleft palate, delayed growth, development, learning, and speech, renal malformations/aplasia (sometimes kidney is missing), poor muscle tone, psych issues such as anxiety and 30x higher risk for schizophrenia

  • there is a lot of phenotypic variability, especially amongst different ethnicities - likely also d/t different del bps

• Mechanism: deletion can be caused from the presence of low-copy repeats leading to NAHR aka SD mediated

  • different 22q deletions exist, most common is 3 Mb

• deletion can be tested for via FISH, but CMA recommended

  • FISH only covers for most common deletion so if negative, fu w/ CMA

Distal or adjacent 22q deletions have very similar phenotypes - aka 22 D-E deletion

• conotruncal heart defects, DD, short, hypospadias, hypertelorism, and bifid uvula (split uvula)

Hemophilia A

Hematology

F8

• X-linked recessive

• Symptoms: excess and long timed bleeding due to minimal clotting factor VIII (8)

• Example Mechanism: extra sequence added into exon 14 which led to altered exon splicing and this a deletion within the F8 gene

Rett Syndrome

NEURO

MECP2 (Xq28)

• X-linked dominant

• present in females, lethal in males

• LOF mutation

• Symptoms: normal development up to 18 months, stagnation, then rapid regression

  • fits of screaming + crying, autism, apnea, gait ataxia, apraxia, tremors, seizures, microcephaly

Prader-Willi vs Angelman Syndrome

PEDS

15q11-13

• caused by segmental duplication mediated breakpoints in 15q

Paternal Expression of PWS, Maternal Repression of PWS

• loss of paternal PWS = Prader-Willi Syndrome

  • Symptoms: poor feeding during infancy followed by uncontrollable hunger in teenage years

Maternal Expression of UBE3A, Paternal Repression of UBE3A

• loss of maternal UBE3A = Angelman Syndrome

  • Symptoms: severe mental retardation, absent to little speech, inappropriate laughter, seizures, jerky ataxic movements, decreased pigmentation (ex. pale blonde babe in brunette tan family)

Mechanism: imprinting

• PWS

  • paternal gene expressed and maternal gene methylated

• ANG

  • maternal gene expressed and paternal gene methylated

Roberts Syndrome

PEDS

ESCO2

• AR

• Symptoms: prenatal growth retardation, limb malformations (on all 4), craniofacial abnormalities

• Mechanism: gene regulates cohesion, which is in charge of binding sister chromatids. mutation in the gene leads to early separation of sister chromatids

Trisomy 21

PEDS

+chr 21

• Symptoms: hypotonia, intellectual disability, upslanted palpebral fissures, epicanthal folds, brachydactyly, cardiac anomalies, duodenal atresia, increased risk of leukemia

Causes

• 90% maternal M1 NDJ

• 10% paternal M2 NDJ

Mechanisms

• 2% mosaic

• 4% translocation (consider for younger parents)

• partial triplications in 21q

Trisomy 13

PEDS

+chr 13 aka Patau Syndrome

• Symptoms: holoprosencephaly, cleft lip and/or palate, cardiac anomalies, growth deficiency, scalp defect, blindness, deafness, postaxial polydactyly

Trisomy 18

PEDS

+chr 18 aka Edwards Syndrome

• Symptoms: growth deficiency, clenched hands, rocker-bottom feet, short sternum, cardiac anomalies, inguinal or umbilical hernia

Wolf Hirschhorn Syndrome

PEDS

terminal 4p deletion (ex. 4p16.3)

• Symptoms: wide nose bridge, widely spaced eyes, microcephaly, IUGR/postnatal growth deficiency, hypotonia, seizures, feeding difficulties, ptosis, distinct EEG abnormality

  • “greek helmet-like” facial shape

Mechanism: 10-15% involve unbalanced translocations

Alagille Syndrome

PEDS

98-99% JAG1 & 1-2% NOTCH2

• AD

• Symptoms: cholestasis, CHD, posterior embryotoxon, prominent forehead, deep set eyes, hypertelorism, pointed chin, vertebral anomalies, renal disease, growth retardation

Emanuel Syndrome

PEDS

+der(22)t(11;22)(q23;q11.2)

• Symptoms: IUGR in fetus (pre and post natal growth deficiency), congenital diaphragmatic hernia, ventricular septal defect, sever ID, microcephaly, ear anomalies, cleft high-arched palate, kidney abnormalities, CHD, genital abnormalities for males

• Mechanism: extra chr 22 caused translocation

Pallister-Killian Syndrome

PEDS

isochromosome 12p (mosaic)

• Symptoms: severe hypotonia, seizures, severe DD, coarse facial features, diaphragmatic hernia, hypo/hyper pigmented streaks on kin

Cystic Fibrosis

PEDS

CFTR

• AR

• variable expressivity

• Symptoms: progressive pulmonary disease, exocrine pancreatic insufficiency, obstructive azoospermia, elvated sweat chloride concentration, growth failure, and meconium ileus

Fragile X

PEDS

FMRI

• trinucleotide repeat expansion - CGG repeats

• sex-specific anticipation (worse when passed from mom)

• Symptoms: ID, neuropsych features, craniofacial features, hyperactivity

  • FXPOI (childhood): primary ovarian insufficiency

  • FXTAS (early to mid adulthood): cerebellar ataxia, intention tremor, cognitive decline

Turner Syndrome

PRENATAL?

45,X (monosomy X)

• nondisjunction

• phenotypic female

• Symptoms: short stature, ovarian dysgenesis, sexual immaturity, cardiac anomalies, renal anomalies (ex. horseshoe kidney), possible hearing issues, normal IQ

• issues of haploinsufficiency in the womb lead to spontaneous abortion in 99% of cases

Klinefelter Syndrome

47,XXY

• nondisjunction of sex chrs

• phenotypic male

  • Symptoms: tall stature, reduced facial and body hair, gynecomastia, MVP, reduced fertility, osteoporosis, possible DD

• increased mortality risk

Congenital Adrenal Hyperplasia (CAH)

• AR

• CYP21A2, on chr 6, p-arm, 21.3

• typically a 46,XX DSD

• Clinical Forms: salt-wasting (SW), simple virilizing (SV), nonclassic (NC) late-onset (ex. attenuated or acquired), and cryptic (75% have salt wasting type which requires immediate treatment)

• Symptoms: high 17-OHP, low 21-hydroxylase, high androgens, ambiguous genitalia (possible micropenis), virilization

• Treatment: immediate care (physically and mentally) can help gender affirmation

Androgen Insensitivity Syndrome

46, XY

muts in androgen receptor gene (AR) on chr X

• Mechanism: incomplete masculinization due to issues with androgen receptors

• male chrs but female external genitalia + breast development

Reasons for DSD is 46,XY “male”

• loss of SRY - female phenotype and gonadal dysgenesis

• DAX1 duplication - female phenotype and gonadal dysgenesis

• SOX9/SOX9 enhancer deletions - female phenotype and gonadal dysgenesis w/ or w/o campomelic dysplasia

• NR5A1 mutation - ambiguous genitalia, XY partial gonadal dysgenesis

• WNT4 duplication - ambiguous genitalia, cryptorchidism (undescended testicles)

• AR mutation - androgen insensitivity leading to female phenotype

Reasons for DSD is 46,XX “female”

• SRY gene translocated onto X - male development (ovotesticular)

• SOX3 duplication - male development (testicular)

• SOX9/SOX9 enhancer over-expression - male development (testicular)

• CYP21A2 mutation (AR) - ambiguous genitalia, virilization, micropenis

Jacob Syndrome

47,XYY - male

• normally phenotypically WT

• Variable Physical Issues: tall, weak, large teeth, macroorchidism (normal testosterone), small penis, increased mortality

• Variable Neurological Issues: speech and language delay, learning difficulties, motor delay, autism like traits, cognitive impairment

• Fertility is normal and offspring are typically chromosomally normal (although thought to be of increased risk)

Trisomy X

47,XXX - female

• Variable Features: typically tall (increased SHOX gene dosage), normal puberty, normal fertility but risk of early ovarian failure, low IQ, hypotonia (low muscle mass), motor, learning and expressive language delay, increased mortality

• Mechanism is often NDJ in maternal M1

Gorlin Syndrome

(hedgehog) mutations in patched

• Symptoms:

  • Face: wide-set eyes, broad nasal saddle, protruding brow or jaw, jaw cysts

    • Hallmark! appearance of basal cell carcinoma

  • Neuro: hydrocephalus, seizures, ID, deafness, brain tissues

  • Eyes: defects w/ iris or lens, blindness

  • Body: bone defects like scoliosis or rib issues

Smith-Lemli-Opitz Syndrome

(hedgehog) mutations in 7-dehydrocholesterol reductase (no cholesterol to make Shh soluble)

• Symptoms: microcephaly, ID, hypotonia, incomplete male genital development, short nose, renal hypoplasia, oral clefting, CHD, cerebellar hypoplasia

  • Hallmark! 2-3 syndactyly, polydactyly

Greig Cephalopholysyndactyly

(hedgehog) mutations in Gli-3 (too much Shh)

• Symptoms: polydactyly, wide thumbs, big toe, cutaneous syndactyly

  • Hallmark! ocular hypertelorism, macrocephaly, high prominent forehead

Pallister-Hall Syndrome

(hedgehog) mutations in Gli-3

• Symptoms: hypothalamic hamartoblastoma (benign tumor), postaxial polydactyly, imperforate anus

  • Hallmark! presence of the small brain tumor and short 4th metacarpals

  • some also have: laryngeal cleft, abnormal lung lobbing, renal issues, short 4th metacarpals, hypoadrenalism, CHD, or IUGR

Noonan Syndrome

(Rasopathy) mutations in Sos, PTPN11, Shp-2, Kras, Raf1

• AD w/ variable penetrance

• Symptoms: hypertelorism, downslanting eyes, low set ears w/ posterior rotation, pulmonic stenosis, short stature, short neck w/ webbing (sign of lymphadema), epicanthic folds, deafness, motor delay, bleeding issues, pectus

  • unique increased risk for juvenile myelomonocytic leukemia (JMML)

*A version exists called Noonan-NF where an NF1 mutation causes Noonan and NF1 symptoms at the same time

Leopard Syndrome

(Rasopathy) mutations in PTPN11

• inheritance?

• Symptoms: lentigines (look like CALs but are all over), abnormal ECHO, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, stunted growth, deafness

Cardiofaciocutaneous Syndrome

(Rasopathy) mutations in Kras, Braf, Mek1, and MEK2

• inheritance?

• Symptoms

  • cardiac: pulmonic stenosis, atrial spectal defect, hypertrophic cardiomyopathy

  • other: high forehead w/ bitemporal constriction, downslanting palpebral fissures, depressed nasal bridge, posteriorly angeled ears

  • cutaneous findings: sparse + friable hair, hyperkeratotic skin lesions, generalized “ichthyosis” looking skin condition

Costello Syndrome

(Rasopathy) mutations in HRAS (only gene)

• inheritance?

• Symptoms: postnatal failure to thrive, short stature, macrocephaly, mental deficiency, abnormal EEG, hypotonia, increased risk of malignant tumors

Neurofibromatosis

NF1

• AD d/t a high spontaneous mutation rate

• Symptoms

  • presence of cafe au lait spots aka CALs

  • presence of Lisch nodules in the iris

  • behavioral problems with learning disability

  • scoliosis

  • optic glioma

Cri du chat

terminal 5p deletion (ex. 5p15; thought to be the location of larengial tissue)

• low birth weight

• rounder, smaller face

• weak cry (“cry of the cat” name)

• hypotonia

• developmental delay/mental retardation

• microcephaly

• epicanthi

• single palmar crease

Mechanism: 15% from unequal segregation of a parental translocation

Williams Syndrome

del of chr 7p11.2 - recurrent 1.7 Mb del

• region include ELN gene, which codes for elastin (explains cardiac phenotype)

Mechanism: segmental duplications leading to misalignment

Symptoms:

• Neurodevelopmental issues with ID, hyper-sociability, and anxiety

  • vibrant talkative personality

• supravalvular aortic stenosis (SVAS), hypertension, hypercalcemia

• short stature, depressed nasal bridge, prominent epicanthal folds, prominent lips, full cheeks, medially flared eyebrows, anteverted nares

Achondroplasia

FGFR3 Group Disorders

*AD

• long + narrow trunk, portruding forehead, midface hypoplasia, brachydactyly w/ trident, excessive skin folds, recurrent ear or sinus infections, sleep apnea, forward rounding @ thoracic + lumbar meet point, delayed milestones

• variable expression

*Foramen Magnum Stenosis: a serious complication of achondroplasia characterized by hypotonia, excessive sweating, sleep apnea, vomiting, upper motor neuron signs and symptoms, sick and irritable appearance

• d/t narrowed area where spinal cord connects to brain/skull

Osteogenesis Imperfecta (Type II Collagen Disorders)

COL1A1 or COL1A2

• Mild form: near-normal stature, hearing loss, blue sclerae, dentinogenesis imperfecta (yellow teeth)

  • frequent breaks heal normally, decline w/ puberty, and increase post-menopausely

• Moderate form

• Severe form (lethal): significantly short stature, high frequency of fractures, scoliosis w/ cardio compromise, triangular face, hearing loss, dentinogenesis imperfecta, grey to blue sclerae

Crouzon Syndrome

FGFR2

• AD

• Symptoms: eyes (proptosis, hypertelorism), midface (hypolasia), body (normal hands + feet)

Frontonasal Dysplasia

ALX1,3,4

• often AR

• symptoms: midline face, hypertelorism, bifid or notched nasal tip, medial cleft of nose or lip, widow’s peak

Bardet-Biedel Syndrome

____ gene

ex. non-motile cilia condition

• Symptoms: rod-cone dystrophy leading to blindness, postaxial polydactyly, truncal obesity, learning difficulties, male hypogenitalism, renal cysts

Alstrom Syndrome

____ gene

ex. non-motile cilia condition

• Symptoms: progressive rod-cone dystrophy, sensorineural hearing loss, childhood obesity, DCM, renal issues

Joubert Syndrome

____ gene

ex. non-motile cilia condition

• Symptoms: Molar tooth sign on brain MRI (hallmark!), ataxia, hyperpnea, abnormal eye + tongue movements, hypotonia, polydactyly, cleft lip or palate, ID, retinitis pigmentosa (RP)