Syndromes/Conditions

Roberts Syndrome

Abnormalities of a gene required for proper sister chromatid alignment and cohesion during S-phase resulting in short stature, limb shortening, and microcephaly

Telomere Syndromes

degenerate disorders presenting from childhood to adulthood in patients with abnormal telomere shortening due to defects in telomerase

Osteogenesis Imperfecta

- "brittle bone"

- dominant/negative

- COL1A1/COL1A2

- variable expressivity

-easy fractures, hearing loss, blue sclera, short stature

Holt-Oram Syndrome

-TBX5*interacts with transcription factors

-Congenital heart defects / Cardiac arrhythmias

-Limb anomalies (asymmetrical / absent thumb / arm abnormalities)

-other skeletal abns.

Congenital Heart Defects

-most common birth defect

-isolated* or syndromic

*many genes id'd as causative are transcription factors or chromatin remodeling factors

Duchenne Muscular Dystrophy

-X-linked or de novo

-caused by large del in 1+ exon(s) causing frameshift and premature truncation

*treatment forces splicing to skip damaged exons and form shorten/partially fxnal protein

-progressive muscle weakness (dilated cardiomyopathy causing death)

Becker Muscular Dystrophy

-Dystrophin gene is partially functional (unlike DMD)

-less severe phenotype

Spinal Muscular Atrophy (SMA)

-Recessive

-Caused by del in SMN1 gene (exon 7) / splice site variant

*treatments involve activating SMN2 to express at higher levels

-Progressive muscular disease w/ motor neuron atrophy

-variable expressivity

Hutchinson Gilford Progeria

-dominant, de novo

- erroneous splice site in exon 11

- abn. LMNA product

(responsible for structural integrity of nucleus)

-premature aging

-short, early CVD, alopecia, abn. skin/nails, distinct facial features

Dyskeratosis Congenita

-multiple inheritance/multiple genes

-problem w/ machinery that maintains telomere length

-nail abnormalities/"lacy" pigment. of skin, and oral leukoplakia

-can have addl. multi-system issues

Turner Syndrome

-X0

-short stature, skeletal diff.

-heart problems

-learning disabilities

-delayed/absent puberty

-horseshoe kidney, webbed neck, lymphedema

-increased risk for autoimmune disease, thyroid/hormone issues, osteoporosis

Ataxia Telangiectasia

-autosomal recessive

-ATM protein (part of homologous DNA repair pathway)

-broad spec. of phenotypes (progress. neuro. degeneration, ocular telangiectasias (cluster of blood vessels), immunodef., and cancer susceptibility)

Fanconi Anemia

-Autosomal Recessive

-Clinically heterogeneous (biallelic pathogenic variants )

-pathway protects against genomic instability (loss of FA pathway leads to chromosomal aberr. w/ increase in radial chromosomes)

-22+genes involved

-improper double-stranded repair

- bm failure, skeletal defects, hypopigmentation, early onset cancer, and renal, cardiac, GI, reproductive systems affected

Xeroderma Pigmentosum

-Autosomal recessive

-biallelic path. variants in NER pathway genes

-increased sensitivity to sunlight / inability to repair UV-induced lesions

-pigment abn., predisposition to skin cancer, and early degeneration of nervous system

Li-Fraumeni Syndrome

-Autosomal dominant

-germline TP53 mutation

-high lifetime cancer risk (higher for women)

-multiple cancer types

Mucopolysaccharidoses (MPS)

-body cannot break down GAGs & they accumulate in lysosomes -progressive disorders

-neurodegeneration, heart disease, coarse facia, short stature, enlarged liver/spleen

Congenital Disorders of Glycosylation (CDGs)

-genes involved in building sugars & attaching them to proteins

-huge range of effects / ? when unexplained & body system matches

-most often neurological, multi-system, DD, hypotonia, liver, eye, skin, skeletal, endocrine, GI, or immuno

Chromatinopathies (general)

-major transcription factors that downstream processes

-abnormal chromatin remodeling, histones

-major facial dysmorph, multi-systems, DD, neuro, poor growth, birth defects, immune, limb anomalies

Cornelia de Lange (CDLS)

-"classic" chromatinopathy

-de novo, dominant (multi-gene ex: NIBPL)

-extremely variable (upturned nose, unibrow, heart, hearing, genital, behavioral, feeding, etc.)

Kabuki Syndrome

-chromatinopathy (dominant, de novo, loss-of-function, multi-gene ex:KMT2D)

-elongated lower lid, extra skin pad, ID, birth defects, poor growth, endocrine, feeding, hearing

Kleefstra Syndrome

-chromatinopathy (de novo, generally dominant)

caused by EHMT1 or del 9q34.3 (same region)

-poor or absent speech, seizures, extreme apathy or catatonia after puberty, severe respiratory infections

Leri-Weill dyschondrosteosis

-caused by SHOX (single variant)

-variable short stature, Madelong deformity, mesomelia

-assoc. w/Turner syndrome

22q11.2 Proximal Microdeletion Syndrome

-most common microdel syndrome

-congenital hear disease (ToF), palate defects, hypocalcemia, seizures (idiopathic or due to hypoCA), immunodeficiency

-learning diff., behavioral diff., expressive/receptive speech delays, & Psych concerns (ex: schizophrenia)

Prader-Willi Syndrome

-paternal loss - control center 15q11q13 (imprint) -hypermethylation/silencing

-DD, failure to thrive & feeding problems as infant -> insatiable appetite when older

-sev. hypotonia, distinct features, short stature

Angelman Syndrome

-maternal loss - control center or UBE3A (imprint) 15q11q13 -hypermethylation/silencing

-ID(severe),ataxia(gait),seizures, non-verbal, happy, microcephaly

Hemoglobinopathies

-abn. amount of any hemo. chain = thalassemia

-abn. structure or function

Sickle Cell Disease

-abnormal beta chain

-when not bound O2, hemo molecules stick together

-get stuck in capillaries cause pain and damage

Hereditary Persistent Fetal Hemoglobin (HPFH)

-genetic variant in promotor -> greater ratio of fetal hemoglobin

-benign, protective effect -> SCD (especially homozygous)

Achondroplasia

-autosomal dominant / gain of function

-impacts fxn of cell surface receptor (ex: FGFR3) attached to tyrosine kinase leading to bone growth signaling being turned off (when receptor kept on)

-homozygous indiv. rarely survive to birth

RASopathies

-group of mostly dominant conditions

-variants of RAS pathway(G proteins/cell prolif pathway)

-affects multi areas of body (heart,brain,eyes,skin,etc.), can cause dysmorphism & tumors (NF1)

Noonan Syndrome

-RASopathy/common/variable

-short stature, hypertrophic cardiomyopathy, features(rough/bumpy skin, curly hair, high forhead, low-set ears, etc.), multi-system

-Rasopathy gene panel (many assoc. genes)

Androgen Insensitivity Syndrome

-non-functional AR gene (androgen receptor, gene on X-chrome)

-complete/partial or mild

-Testes develop partially or fully/testosterone produced normally, does not respond to androgens, appear externally female (testes remnants internal) or ambiguous genitalia, abn. female puberty/absent periods

Tay-Sachs disease

-autosomal recessive disorder (pediatric onset 3-6mo)

-Malfxn HexA protein in lysosome (cannot break down sugar in ganglioside/remove GalNac) -Ganglioside accumulates in lysosome -> cell death/malfxn

-progressive neurodegeneration (normal develop.-> loss of motor skills/bodily fxns), seizures, hypotonia, cherry red spot in retina

-death in childhood (~ by 5 yrs)

Barth Syndrome

-X-linked (lipid synthesis disorder)

-Cardiolipin is incorrectly formed (mitochondrial membrane not fully functional -> heart/skeletal muscle) -due to tafazzin variant which helps synthesize/remodel fatty acid chains

-leads to poor energy metabolism/mitochondrial disease

-Cardiomyopathy, Neutropenia (risk of infection), Growth delay, & low 5-year survival

I-Cell Disease

-rare recessive disorder (infantile or later-onset)/progressive

-Glycosylation/Phosphorylation error (GNPTAB protein responsible for adding mannose 6-phosphate group to N-linked glycoproteins in Golgi)-> erroneous trafficking (glycoproteins follow secretory pathway into extracellular space)-lack of enzymes in lysosome -> cell debris building up in lysosome

-multisystem (coarse feature, poor growth, sketetal, cardiac,

airway, etc.)

Familial Hypercholesterolemia (FH)

dominant (can be homozygous - more severe)

-multi-gene result in lack of LDLR at cell surface

-problem with LDL uptake

-increase cholesterol levels in blood

-risk of heart attack, cholesterol deposits in skin

Cystic Fibrosis

-recessive disorder (carriers may have mild symptoms)

-impairs chloride channels, poor ion movement

-affects cells that produce mucus/sweat/dig. juices

- sent to proteosome, very few on surface) /med. that lowers temp. corrects multiple folding errors -> mild CF

Beckwith-Wiedemann Syndrome (BWS)

-imprinting disorder (loss of maternal methylation, CDKN1C, or overexpression paternal, or related mutations) / 11p15.5 maternal copy has loss or mutation (vast majority), if inherited, would be from mother

-rare to have increased recurrence risk (cyto only) / majority sporadic

-overgrowth, asymmetric growth (hemihyperplasia), macroglossia, increased risk for embryonic tumors, omphalocele (GI herniates into embilical cord)

Silver-Russell Syndrome (SRS/RSS)

-majority of causes unknown (rest: loss of paternal methylation on 11p15.5 or maternal UPD on chrome 7) *over-abundance of maternal input of a couple chrom. regions (if inherited would be from mother)

-primordial dwarfism,body asymmetry,relative macrocephaly,feeding diff.,triangular face/large forhead

Fragile X Syndrome

-X-linked (FMR1 gene) / trinucleotide repeat disorder CGG (promotor region), inherited from mother -> increase risk of anticipation (>200 is pathologic) /genotype-phenotype correlation

-develop. disorder, common cause of inherited ID/autism, large ears, macrocephaly, long face

*premature ovarian insufficiency in carriers poss.

Fragile X Tremor Ataxia Syndrome (FXTAS)

-premutation syndrome / more common in males

-older adult onset (after age 50)

-increased likelihood w/more CGG repeats (mRNA toxicity)

-progressive, tremor, dementia, walking issues

Alkaptonuria

-enzyme deficiency: homogentisic dioxygenase / Phenylalanine & Tyrosine degradation pathway

-autosomal recessive (ID'd by Garrod)

-dark tissue/urine due to accumulation of homogentistic acid

-treatments:NTBC (blocks conversion to substrate/reduces substrate) & Vitamin C (inhibits deposition of HGA in connective tissues)

Phenylketonuria (PKU)

-deficient enzyme: phenylalanine hydroxylase (PAH) <- PAH gene / autosomal recessive

-PHE (substrate) accumulates in brain / neurotoxic in high amounts

-well-appearing for 2-3mos, then irreversible DD/ID, with possibility of seizures, rash, fair skin/hair (lack of tyrosin -> melanin), musty odor due to phenylketones

Amino Acid Disorders (general)

-body cannot break down protein/aas for energy properly

-problems w/ intestinal absorption, renal excretion & reabsorption & synthesis into functional proteins

-toxic metabolites build up (symptoms due to toxicity or deficiency)

ex: PKU, MSUD, alkaptonuria

Maple Syrup Urine Disease (MSUD)

-deficient enzyme: BCKAD (branched chain alpha-ketoacid dehydrogenase) -> enzyme complex found in mitochondria (4 subunits) - purpose is to break down branch chain aas

*leucine is neurotoxic (alloisoleucine present = pathognomonic for MSUD)

-build-up of organic acids in urine (2-oxoisocaproic acid = neurotoxin / biproduct)

-recessive (common in plain clothes pop) -> "fussy"

-metabolic acidosis, hypoglycemia, ketonuria, encephalopathy, cerebral edema, ab. brain dev.

Maternal PKU Syndrome

-teratogenic effect of elevated PHE during preg.

-mom's liver/placenta metabolizes macronutrients for fetus ->concentrates PHE (1.5x maternal blood)

-results in birth defects: ID, microcephaly, IGR, CHD, & dysmorphic features

Homocystinuria

-deficient enzyme: CBS (common)

-results in elevated homocysteine & methionine

-50% are B6 responsive (if don't have complete CBS absence)

-challenging to dx (homocysteine is target and can be normal/borderline for testing)

-eye(myopia, ectopia lentis*downwards dislocation),tall stature, Marfanoid habitus, osteoporosis, scoliosis, pectus carinatum or excavatum, genu valgum (knock-knees), blood clots, DD, seizures, psych. problems

-treatment: low protein, methionine-free, cofactors, oral betaine, ER protocol for stroke and blood thinning meds (adults)

Nonketotic Hyperglycinemia (NKH)

-deficient activity: glycine cleavage system (complex enzyme w/ multiple subunits)

-causes elevation of glycine -> excitatory neurotoxin -> seizures

-autosomal recessive /biallelic path variants (locus heterogeneity)

-apnea, "hiccups"/seizures(prenatal,neonatal,postnatal)

-progressive lethargy, hypotonia

-severe ID, shortened lifespan

-Treatment: no curative! anti-epileptic, ketogenic diet

Cleidocranial Dysplasia (CCD)

-hypoplastic/absent collarbones, dental anomalies, wide/open fontanelles

-sequence RUNX2

22q11.2 Distal Microdeletion syndrome

Distinguishing features: Less likely to have palate diff., hyperCA, less notable facial features, mental health concerns or autism / more likely ADHD

-Congenital heart disease, feeding/swallowing diff., poor growth
-developmental delays, ADHD, anxiety, learning diff.

Phelan-McDermid syndrome (PMS)

22q13 microdel syndrome (both SHANK3 main contributor to AD phenotype / ARSA is AR)

*absent or very poor speech & decompensation/catatonia in adulthood

-feeding diff., congenital heart defects, tall/accelerate growth, CNS, seizures, renal abn., global developmental delay, gait abn., ASD, aggressive behavior, mental health disorders, neuropsych. decomp./regression

22q11.2 Duplications

-genes don’t report triplosensitivity (often inherited ~70% from unaffected parent)

*similar phenotype but not as significant as dels

-CHDs, palatal anomaly, DD, behavior concerns (variable)

22q12-q13-qter duplication syndromes

-often due to unbalanced translocation in parent (not correlated w/size)

-SHANK3 may have triplosensitivity??

-poor growth, clefting, CHD, renal abn., GU abn., DD, ID mild (variable)

Williams syndrome

7q11.23 del syndrome (ELN gene) most often de novo

-”elfin-like” features (broad forehead, wide mouth, thick vermillion, gaunt appearance, etc.)
-congenital heart defect (supravalvar aortic stenosis), failure to thrive, connective tissue dysfunction, learning diff., strong language skills (“cocktail personality”), early puberty, premature greying, short stature

7q11.23 duplication syndrome

30% inherited from mildly affected parent

-”normal” infancy, DD including speech delays (opposite of WS), behavior concerns, learning diff.

1p36 deletion syndrome

>5 Mb (cytogenetically visible) includes SKI, RERE, PRDM16 / mostly de novo

-Skull diff. (brachy, micro, craniosynostosis), DD (absent speech), CNS (w/ or w/o seizures), behavioral (including self-injurious), CHDs, dilated cardiomyopathy (acquired), obesity

Wolf Hirschhorn syndrome

4p- / WHSCR1 = LETM1 included → seizures / WHSCR2 haploinsuff ?

*de novo often paternal in origin

-”Greek warrior helmet” appearance, microcephaly, poor growth, DD, lifelong congenitive deficits

5p deletion syndrome

aka Cri du Chat syndrome (SEMA5A, CTNND2) / phenotypes mapped but genes not well understood

*mostly de novo of paternal origin (15% familial translocations)

-specific infantile cry, microcephaly, poor growth, features coarsen w/ age, CHDs, DD, lifelong cong. deficits

Langer-Gideon syndrome

tricho-rhino-phalangeal syndrome (type 2), 8q24.11-q24.13 deletion

-thin hair, broad nose, short meta_ bones, cone-shaped epiphyses, bony growths (joint deformations), DD

Potocki-Shaffer syndrome

11p11.2p12 deletion syndrome (de novo)

-craniosynostosis (brachycephaly), facial asymmetry, bony growths (joint deformations), CNS abn., seizures, variable cog. deficits

WAGRO syndrome

11p13 deletion (PAX6 and WT1) / de novo or inherited balanced translocation

-Wilms Tumor, aniridia (cataracts, ptosis, vision loss), genitalia (hypospadias, etc.), slow growth, variable DD, obesity

Angelman syndrome

maternal 15q11q13 deletion (UBE3A) *dels most severely affected / maternal inherited translocation possible

-microcephaly, hypopigmentation (in del), cog. deficits, nonverbal, gross motor delays, seizures, inappropriate laughing/smiling

Prader Willi syndrome

paternal 15q11q13 deletion (MAGEL2) / deletion, UPD, or imprinting center defect possible

-severe neonatal hypotonia & feeding difficulties, excessive eating after 4y, DD (mild cog. deficits), short, morbid obesity, behavioral concerns (stubborn, manipulative, OCD), high mortality (central adrenal insuff.?)

Miller-Dieker syndrome

17p13.3 deletion (larger dels → cyto. visible & more profound med. concerns) / LIS1,PAFAH1B1 genes

d. by 2y (always de novo syndrome but parent may have b. trans)

-microcephaly, FTT, sig. CNS anomalies, seizures, spasticity, sig. DD, profound cog. deficits

Smith-Magenis syndrome (SMS)

17p11.2 deletion (RAI1, FLCN, PMP22) / can have seq. variant in RAI1

inverted circadian rhythm of melatonin & insertion of foreign bodies (w/ RAI1 more common)

-specific facies (coarsen over time), DD, mild/mod. cog. deficits, manipulative/self-injurious behavior, short, obesity

1p21.1 deletion syndrome

-genes: GJA5, GJA8, HYDIN (*typically inherited*)

-not clinically recog. / “new” / incomplete pen. & variable express.

-microcephaly, mild dysmorphic features, DD, mild cog. deficits, behavioral concerns

1p21.1 duplication syndrome

-HYDIN (no triplosensitiivity reported w/ other genes)

-not clinically recognized / incomplete pen. & variable express.

-Macrocephaly (opposite), DD, learning difficulties, behavior concerns, scoliosis, short

3q29 deletion syndrome

-PAK2 (typically de novo)

-*lifelong GI dysfunction*

-DD, mild-mod. cog. deficits, behavioral concerns (including psychosis), feeding difficulties, FTT

Kleefstra syndrome

9q34.2 deletion (EHMT1/KMT1D) / de novo or inherited (mosaic poss.)

*non-verbal (severe expressive speech delay), catatonic, progressive apathy

-DD, lifelong cog. deficits, behavioral (psychiatric, ASD), CNS abn., seizures, CHDs, GI anomalies

15q11.2 microdeletion syndrome

NIPA1, NIPA2, CYFIP1,TUBGCP5 (do not include PWS/AS region)

-not clinically recognizable / incomplete pen. & variably express.

-DD (speech delay), learning differences, cog. deficits, behavioral concerns, CNS abn. (w/ or w/o seizures)

15q13.3 microdeletion syndrome

hetero/homozygotes both possible / KLF13, CHRNA7 (AS/PWS not included)

-DD, cog. deficits, behavioral concerns, CNS abn. (imaging & seizures poss.), congenital heart defects, subtle facial differences

Maternal 15q duplication syndrome

-larger 15q duplication (either maternal isodicentric 15q11.21q13.1 most common or maternal interstitial duplication 15q11.2q13.1

-idic can be seen cytogenetically, always de novo & lead to more severe impact (interstitial can be inherited)

-hypotonia, gross motor delay, DD, cog. deficits, behavior concerns, seizures, EEG is “characteristic”

16p11.2 proximal microdeletion syndrome

MAZ1 (typically de novo)
-not clinically recognizable / incomplete pen. & variable express.

-DD, motor speech disorders (apraxia, dysarthria), impaired language, behavioral concerns, childhood obesity, seizures

16p11.2 proximal microduplication

MAZ1

-incomplete pen. / variable express. (typically not clin. recognizable)

-DD (more variable than del), behavioral concerns (ASD more common), decreased BMI (opposite of del)

16p12.2 microdeletion syndrome

UQCRC2, CDR2, EEF2K (*Typically inherited*)

-incomplete pen. & VERY variably express. (not clin. recog. condition)

-DD, lifelong cog. deficits (mild-profound), behavioral concerns (ASD, psychiatric, fam hx of psych.)

17q12 deletion syndrome

HBF1B, LHX1 (typically de novo)

-highly prevalent w/ variable expressivity

congenital anomalies of kidneys & urinary tract (CAKUT)*, hyperparathyroidism, external GU anomalies, Mullerian aplasia

-Behavioral concerns, DD

17q12 duplication syndrome

-no triplosensitivity in genes (*typically inherited*)

-DD (speech delay), cog. deficits, behavioral, seizures, microcephaly, short stature

Koolan deVries syndrome (KdVS)

17q21.31 microdeletion (KANSL1 & CRHR1) - can have mutation in KANSL1 / typically de novo

-characteristic facies, DD, cog. deficits, behavioral profile (friendly/social), epilepsy, CHD, renal, skeletal diff.