Molecular/Genetic Testing Strategies & Gene Associations

22q11.2 proximal microdel syndrome (Molecular Test Strategy)

1. SNP Microarray (exact bap points for del)

2.qPCR or FISH (quick confirmation of del presence - limited to regions screened)
3. Karyotype? (only if large enough to pick up)

Size of 22q11.2 del syndrome “Typical” Deletion

Typical del = 2.5 to 3Mb (LCR A-D)
30-40 genes / 90% of indiv. w/ del de novo

Size of 22q11.2 del syndrome “Atypical” Deletion

Atypical del = ~1.5 Mb (LCR A - C)
20-30 genes / typically inherited from unaffected/mildly affected parent

Size of 22q11.2 del syndrome “Distal deletion”

Distal del = 1-2 Mb
25-40 genes / inheritance depends on size of del (larger = more likely de novo)

Genes Associated w/ 22q11.2 Proximal Microdel syndrome

PRODH, SNAP29, TXB1, DGCR8, CRKL

Genes Associated w/ 22q11.2 Distal Microdel syndrome

CRKL, MAPK1, SMARCB1

Langer-Gideon syndrome Gene-Phenotype Associations

TRPS1 = trichorhinophalangeal
EXT1 = multiple exostoses
RAD21 = short stature and ID

Potocki-Shaffer syndrome Gene-Phenotype Associations

EXT2 = multiple exostoses

ALX4 = persistent, enlarged parietal foramina

PHF21A = ID and craniofacial differences

Gene-Phenotype Associations for WAGRO syndrome

PAX6 = aniridia
WT1 = Wilms tumor

15q11q13 deletion imprinting syndromes distribution

Angelman → del, point mutation, or IC defect on maternal allele
PWS → del or IC defect on paternal allele

*reverse UPD can also lead to condition (ex: paternal UPD → Angelman and maternal UPD → PWS) /

Miller-Dieker syndrome Gene-Phenotype Associations

Both LIS1 & PAFAH1B1 → lissencephaly, complete agyria (smooth cerebral surface lacking normal folds and grooves), pachygyria (abn. thick, broad, & fewer folds in brain)
*issues with neuronal migration

Smith-Magenis syndrome Gene-Phenotype Associations

RAI1 = craniofacial & behavioral diff. (neuro symptoms)

FLCN = Birt-Hogg-Dubbe

PMP22 = present in larger deletions / assoc. w/ neuropathy/HNPP

Phelan-McDermid syndrome Gene-Phenotype Association

SHANK3 = ASD, mental health & psychiatric dx

1q21.1 deletion syndrome genotype-phenotype associations

GJA5 = cardiac concerns
GJA8 = developmental eye disorders
HYDIN = head circumference

3q29 deletion syndrome genotype-phenotype associations

PAK2 = neuronal migration & differentiation

Kleefstra syndrome genotype-phenotype associations

EHMT1/KMT1D = facial features, cognitive, & behavioral profile

15q13.3 microdeletion syndrome genotype/phenotype associations

KLF13 = CHDs
CHRNA7 = neurodevelopmental diff., epilepsy, abn. EEG

16p12.2 microdeletion syndrome genotype-phenotype associations

UQCRC2 = mitochondrial respiratory chain
CDR2 = cerebellar ataxia
EEF2K = learning & memory

17q12 deletion syndrome genotype-phenotype associations

HBF1B = renal, urogenital, endocrine

LHX1 = GU anomalies, neurodevelopmental diff.

Koolan deVries syndrome genotype-phenotype associations

KANSL1 = ID, hypotonia, facial features
MAPT = frontotemporal dementia
CRHR1 = stress responses