Medical Genomics: Syndromes, Genes, and Key Features

What is the genetic etiology of Down syndrome (T21)?

Nondisjunction (95%), Translocation (4%), or Mosaicism (1%)

What are the key features of Down syndrome (T21)?

Mild-to-moderate ID, developmental delays, hypotonia, and distinct physical features (long palpebral fissures, depressed nasal bridge, single palmar crease)

What is the genetic etiology of Klinefelter syndrome?

47,XXY (Nondisjunction)

What are the key features of Klinefelter syndrome?

Tall stature, hypogonadism, azoospermia (infertility), and gynecomastia

What is the genetic etiology of Turner syndrome?

45,X (Monosomy X) or mosaicism

What are the key features of Turner syndrome?

Cystic hygroma (prenatal), webbed neck, bicuspid aortic valve, coarctation of the aorta or other left sided heart defects, POI

What is the genetic etiology of Emmanuel syndrome?

Supernumerary derivative chromosome 22 from parental t(11;22)

What is the genetic etiology of Cri-du-Chat syndrome?

5p deletion

What are the key features of Cri-du-Chat syndrome?

High-pitched mewing cry, microcephaly, hypotonia, ID and severe expressive language delay, congenital heart defects

What is the genetic etiology of Wolf-Hirschhorn syndrome?

4p deletion

What are the key features of Wolf-Hirschhorn syndrome?

"Greek warrior helmet" facies (prominent glabella, broad nasal bridge), Growth restriction (IUGR), microcephaly, hypotonia, epilepsy, mild-moderate intellectual disability, ASD is most common heart defect

What is the genetic etiology of Pallister-Killian syndrome?

Mosaic tetrasomy 12p (isochromosome 12p)

What are the key features of Pallister-Killian syndrome?

Sparse hair at the temples, congenital diaphragmatic hernia, severe to profound ID, seizures, skin findings consistent with mosaicism

What is an important testing consideration for Pallister-Killian syndrome?

Blood karyotype is often normal; diagnosis requires skin fibroblast or buccal swab.

What is the genetic etiology of emmanuel syndrome?

Supernumerary derivative chromosome 22 causing partial trisomy of 11q and 22q , usually inherited from a parent with a balanced t(11;22) translocation

What are the key features of emmanuel syndrome?

IUGR/postnatal growth deficiency, microcephaly, hypotonia, severe developmental delay/ID, multiple congenital anomalies (cardiac, renal, genital), preauricular pits/tags

What are the key features of 22q11.2 deletion syndrome (digeorge/Velocardiofacial syndrome)?

Conotruncal heart defects (TOF, IAA), cleft palate/VPI, hypocalcemia, immunodeficiency, learning disabilities, schizophrenia

What is an important clinical fact about 22q11.2 deletion syndrome?

It is the most common microdeletion; increased risk for adult schizophrenia.

What genes are associated with 22q?

22q11.2 microdeletion; TBX1 is the key gene in the area of deletion

What is the inheritance pattern of 22q?

Autosomal dominant; de novo

smaller deletions more often inherited

what is the genetic etiology of Distal 22q11.2 Deletion Syndrome?

Autosomal dominant; deletion involves CRKL, MAPK1, SMARCB1.

What are the key features of Distal 22q11.2 Deletion Syndrome?

CHD, feeding difficulty, poor growth, developmental/speech delay, ADHD, anxiety; milder than proximal deletion.

What is the genetic etiology of WAGR syndrome?

usually de novo; 11p13 deletion (WT1, PAX6, and sometimes BDNF)

What are the key features of WAGR syndrome?

Wilms tumor, Aniridia, GU anomalies, ID, and Obesity (if BDNF is deleted)

What is the genetic etiology of Angelman syndrome?

usually de novo; 15q11.2-q13 maternal loss (deletion, UBE3A mutation, paternal UPD, or imprinting defect)

What are the key features of Angelman syndrome?

Severe ID, absent speech, ataxia, and "happy puppet" demeanor (frequent laughter/smiling)

What is the genetic etiology of Prader-Willi syndrome?

usually de novo; 15q11.2-q13 paternal loss (deletion, maternal UPD, or imprinting defect)

What are the key features of Prader-Willi syndrome?

Severe neonatal hypotonia, childhood hyperphagia leading to obesity, hypogonadism, mild intellectual disability, short stature, OCD-type behaviors

What is the geentic etiology associated with williams syndrome?

Usually de novo; 7q11.23 microdeletion (1.5-1.8 Mb); ELN (elastin) is the key gene

What are the key features of Williams syndrome?

Elfin facies, Supravalvular aortic stenosis (SVAS), failure to thrive, and "cocktail party" personality, connective tissue phenotypes

What is the genetic etiology of Miller-Dieker Syndrome?

Usually de novo; 17p13.3 deletion involving PAFAH1B1 & LIS1

What are the key features of Miller-Dieker Syndrome?

Severe lissencephaly, microcephaly, seizures, profound developmental delay, poor prognosis (death by ~2 years).

What is the genetic etiology of Smith-Magenis Syndrome?

Usually de novo; 17p11.2 deletion (RAI1) or RAI1 sequence variant

What are the key features of smith-magenis syndrome?

Developmental delay/ID, inverted circadian melatonin rhythm, self-injurious behaviors (polyembolokoilamania, onychotillomania).

what is the genetic etiology of Phelan-McDermid Syndrome?

22q13 deletion involving SHANK3

what are the key features of Phelan-McDermid Syndrome (22q13 Deletion)?

Severe developmental delay, minimal/absent speech, hypotonia, autism, decreased pain sensitivity, seizures.

what is the genetic etiology of Kleefstra Syndrome?

9q34.3 microdeletion or EHMT1 pathogenic variant.

What are the key features of Kleefstra Syndrome?

Global developmental delay/ID, severely impaired/absent speech, hypotonia, seizures, apathy/catatonia after puberty.

What is the genetic etiology of Cornelia de Lange syndrome (CdLS)?

NIPBL (most common), SMC1A, SMC3, RAD21, or HDAC8 (cohesin pathway)

What are the key features of Cornelia de Lange syndrome (CdLS)?

Synophrys, long eyelashes, pre/postnatal growth restriction, upper-limb (radial) anomalies, developmental delay/ID, self-injurious behavior

What is the genetic etiology of Kabuki syndrome?

KMT2D (most common) or KDM6A (X-linked, rare)

What are the key features of Kabuki syndrome?

Long palpebral fissures, persistent fetal fingertip pads, developmental delay/mild-moderate ID, poor postnatal growth, feeding difficulties, immunodeficiency

What is the genetic etiology of Rubinstein-Taybi syndrome?

CREBBP (most common) or EP300

What are the key features of Rubinstein-Taybi syndrome?

Broad thumbs and broad great toes, beaked nose, characteristic "grimacing" smile, variable intellectual disability, congenital heart defects

What is the genetic etiology of CHARGE syndrome?

CHD7 pathogenic variants (~98% sequence variants)

What are the key features of CHARGE syndrome?

Coloboma, heart defects, choanal atresia, growth/developmental delay, genital anomalies, ear anomalies/hearing loss

What is the genetic etiology of VACTERL association?

Etiology largely unknown (association, not a single gene); screen for Fanconi anemia

What are the key features of VACTERL association?

Vertebral anomalies, Anal atresia, Cardiac defects, TE fistula, Renal anomalies, Limb (radial ray) anomalies (requires ≥3 features)

What is the genetic etiology of Alagille syndrome?

JAG1 (~94%) or NOTCH2 (~2.5%)

What are the key features of Alagille syndrome?

Cholestasis/paucity of intrahepatic bile ducts, peripheral pulmonary stenosis, posterior embryotoxon, butterfly vertebrae, characteristic facies

What is the genetic etiology of Coffin-Siris syndrome?

multiple genes most often ARID1B

What are the key features of Coffin-Siris syndrome?

Hypoplastic/absent 5th fingernails or toenails, developmental delay/ID, coarse facial features, hypertrichosis, feeding difficulties

What is the genetic etiology of OAV/Goldenhar spectrum?

Complex/heterogeneous 1st and 2nd pharyngeal arch disorder; MYT1, AMIGO2, ZYG11B, ZIC3 in some

What are the key features of OAV/Goldenhar spectrum?

Hemifacial microsomia, microtia/anotia, preauricular tags/pits, epibulbar dermoids, eyelid coloboma, vertebral anomalies

What is the genetic etiology of Treacher Collins syndrome?

TCOF1 (63-93%), POLR1D, POLR1B, or POLR1C

What are the key features of Treacher Collins syndrome?

Downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear abnormalities, conductive hearing loss

What is the genetic etiology of Familial Hypercholesterolemia (FH)?

LDLR (60-80%), APOB (1-5%), or PCSK9 (0-3%)

What are the key features of Familial Hypercholesterolemia (FH)?

Markedly elevated LDL-C, xanthomas, and premature coronary artery disease

What is the genetic etiology of Transthyretin amyloidosis (ATTR)?

TTR gene pathogenic variants

What are the key features of Transthyretin amyloidosis (ATTR)?

Restrictive/infiltrative cardiomyopathy, peripheral/autonomic neuropathy, bilateral carpal tunnel syndrome, GI symptoms, renal disease

What is the genetic etiology of Dilated Cardiomyopathy (DCM)?

Highly heterogeneous (AD, AR, X-linked); TTN truncating variants (15-20%), LMNA (6%), MYH7 (4%)

What are the key features of Dilated Cardiomyopathy (DCM)?

LV dilation with thinned walls, reduced ejection fraction (<50%), heart failure symptoms, arrhythmias

What is the genetic etiology of Hypertrophic Cardiomyopathy (HCM)?

Predominantly Autosomal Dominant; MYBPC3 (~50%) and MYH7 (~30-35%)

What are the key features of Hypertrophic Cardiomyopathy (HCM)?

LV wall thickening (≥15 mm), diastolic dysfunction, chest pain/syncope, risk of sudden cardiac death

What is the genetic etiology of Arrhythmogenic right ventricular cardiomyopathy (ARVC)?

Desmosomal genes (PKP2 most common, 20-46%)

What are the key features of ARVC?

Fibrofatty replacement of ventricular myocardium, ventricular arrhythmias, palpitations/syncope, sudden cardiac death

What is the genetic etiology of Restrictive Cardiomyopathy (RCM)?

Sarcomere genes (MYH7, TNNI3); many cases secondary/acquired (e.g., amyloidosis)

What are the key features of Restrictive Cardiomyopathy (RCM)?

Stiff, noncompliant LV with diastolic dysfunction, normal/near-normal EF, biatrial enlargement, heart failure

What is the genetic etiology of Left Ventricular Non-Compaction (LVNC)?

Variable; LDB3 (~5%); associated with Barth syndrome (TAZ, X-linked)

What are the key features of Left Ventricular Non-Compaction (LVNC)?

Prominent LV trabeculations with deep intertrabecular recesses; may be asymptomatic, cause arrhythmias, or heart failure

What is the genetic etiology of Long QT Syndrome (LQTS)?

KCNQ1 (LQT1; 30-35%), KCNH2 (LQT2; 25-30%), SCN5A (LQT3; 5-10%)

What are the key features of Long QT Syndrome (LQTS)?

Prolonged QT interval, syncope, seizures, torsades de pointes, ventricular fibrillation, sudden cardiac death

What is the genetic etiology of Brugada syndrome?

AD (SCN5A)

What are the key features of Brugada syndrome?

Type 1 Brugada ECG pattern, syncope, ventricular fibrillation, sudden cardiac death (often during sleep/rest)

What is the genetic etiology of CPVT?

AD (RYR2) or AR (CASQ2)

What are the key features of CPVT?

Exercise/emotion-induced ventricular tachycardia, syncope, bidirectional VT, normal resting ECG

What is the genetic etiology of Fragile X syndrome?

X-linked dominant (FMR1)

What are the key features of Fragile X syndrome?

Most common inherited cause of ID/ASD, characteristic physical features, premature ovarian insufficiency or FXTAS (tremor/ataxia)

What is the genetic etiology of Rett syndrome?

X-linked dominant (MECP2)

What are the key features of Rett syndrome?

Normal early development, regression with hand-wringing/clapping, then stabilization with microcephaly, seizures, and ASD features

What is the genetic etiology of Holoprosencephaly?

AD or Chromosomal (trisomy 13)

What are the key features of Holoprosencephaly?

Microcephaly, developmental delay/ID, seizures, cleft lip/palate, facial anomalies correlating with brain malformation

What is the genetic etiology of Neural Tube Defects (Anencephaly/Spina Bifida)?

Multifactorial

What are the key features of Neural Tube Defects (Anencephaly/Spina Bifida)?

Anencephaly (lethal); spina bifida (meningocele to myelomeningocele with paralysis/Chiari II/hydrocephalus)

What is the genetic etiology of Septo-Optic Dysplasia?

Typically sporadic

What are the key features of Septo-Optic Dysplasia?

Optic nerve hypoplasia, hypopituitarism (growth hormone deficiency), absent septum pellucidum/corpus callosum agenesis (need ≥2)

What is the genetic etiology of PTEN Hamartoma Tumor Syndrome?

AD (PTEN)

What are the key features of PTEN Hamartoma Tumor Syndrome?

Macrocephaly, autism/ID, hamartomas/lipomas, oral papillomas, GI polyps, increased cancer risk

What is the genetic etiology of Lissencephaly?

AD (LIS1, TUBA1A) or X-linked (DCX)

What are the key features of Lissencephaly?

Severe developmental delay/ID, epilepsy (esp. infantile spasms), hypotonia progressing to hypertonia, microcephaly

What is the genetic etiology of Dandy-Walker malformation?

Often multifactorial; can be part of syndromes

What are the key features of Dandy-Walker malformation?

Vermian hypoplasia, cystic dilation of 4th ventricle, enlarged posterior fossa, hydrocephalus

What is the genetic etiology of Joubert syndrome?

AR

What are the key features of Joubert syndrome?

Molar tooth sign on MRI (hallmark), neonatal hypotonia, ataxia, developmental delay/ID, oculomotor apraxia, episodic apnea/hyperpnea

What is the genetic etiology of Alzheimer's disease?

Multifactorial (AD for early-onset familial forms)

What are the key features of Alzheimer's disease?

Progressive memory loss, cognitive decline, loss of ADLs; β-amyloid plaques and tau tangles

What is the genetic etiology of Parkinson's disease?

Multifactorial (AD/AR for rare early-onset forms)

What are the key features of Parkinson's disease?

TRAP (Tremor, Rigidity, Akinesia/bradykinesia, Postural instability), dementia/psychosis

What is the genetic etiology of ALS?

Mostly sporadic; AD (C9orf72, SOD1)

What are the key features of ALS?

Upper + lower motor neuron signs (weakness, atrophy, fasciculations), dysarthria/dysphagia, respiratory failure