123 Syndromes and their Gene/Inheritance Flashcards
Deletion on 22q11.2 (3-mB del most common)
Gene: TBX1
AD, 93% de novo
22q11 Deletion Syndrome
JAG1, NOTCH2
AD
Alagille Syndrome
SCN5A
(Pathogenic variants in 22 other genes : ABCC9, CACNA1C, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND2,
KCND3, KCNE5, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN10A, SEMA3A, SLMAP, and TRPM4, each <1%)
AD except KCNE5 - XLR
Brugada Syndrome
BRAF, MAP2K1, MAP2K2, KRAS
AD
Cardio-Facio-Cutaneous Syndrome
HRAS
AD
Costello Syndrome
ACVRL1, ENG, GDF2, SMAD4
AD
Hereditary Hemorrhagic Telangiectasia
TBX5, SALL4 (related disorder)
AD
Hold-Oram Syndrome
PTPN11, RAF1, BRAF, MAP2K1
AD
Noonan Syndrome w/Multiple Lentigines (NS-ML, formerly known as LEOPARD Syndrome)
PTPN11, SOS1, KRAS, RAF1, NRAS, CBL, SHOC2, BRAF, RIT1, SOS2, MAP2K1
AD
Noonan Syndrome
7q11.23 Deletion
Contiguous gene deletion syndrome, ELN in the critical region
AD most de novo
William Syndrome
ATM
AR (carriers have increased risk of breast, colon and pancreatic)
Ataxia-Telengiectasia
BLM
AR (1/100 carrier freq in Ashkenazi Jewish)
Bloom Syndrome
FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG (Fanconi anemia group A, B, C, D2, E, F, and G protein; 16q24.3, Xp22.3, 9q22.3, 3p25.3, 6p22-21, 11p15, and 9p13)
FA-D1 - BRCA2 (Breast cancer type 2 susceptibility protein, 13q12.3)
BRIP1 (Fanconi anemia group J protein, 17q22)
FANCL (E3 ubiquitin-protein ligase FANCL)
AR, AD (RAD51), XLR – FA-B
Fanconi Anemia
FBN2
AD
Congenital Contractural Arachnodactyly (Beals Syndrome)
COL5A1 and COL5A2
AD
EDS Classic Type (Type I and II)
Unknown Gene
AD
EDS Hypermobility Type (Type III)
COL3A1
AD
EDS Vascular Type (Type IV)
PLOD1
AR
EDS Kyphoscoliotic Type (Type VI)
TGFBR1, TGFBR2, SMAD3, TGFB2
AD
Loeys-Dietz Syndrome
FBN1
AD
Marfan Syndrome
GJB6
AD
Hidrotic Ectodermal Dysplasia 2
EDA, EDAR, EDARADD
XL (EDA:95%), AD or AR (5%)
Hypohidrotic Ectodermal Dysplasia
IKBKG (aka NEMO)
XLD (most male fetuses miscarry)
Incontinentia Pigmenti
TYR (OCA1), OCA2, TRYP1, SLC45A2, GPR143 (Ocular)
AR, XLR (GPR143)
Oculocutaneous Albinism
NROB1
XLR
X-Linked Adrenal Hypoplasia Congenita
CYP21A2
AR
21 Hydroxylase Deficiency (CAH)
AR
XLR
Androgen Insensitivity Syndrome (Testicular Feminization)
KAL, FGFR1
XLR, AD
Kallman Syndrome Type 1 and 2
XXY
Klinefelter Syndome
GNAS
Sporadic
McCune-Albright Syndrome
HYMAI, PLAGL1
UPD isodisomy chromosome 6, paternal 6q24 duplication, or 6q24 methylation defect
Transient Neonatal Diabetes Mellitus
X genes that escape inactivation, SHOX
Sporadic
Turner Syndrome
FOXL2
AD, 50% de novo
Blepharophimosis, Ptosis & Epicanthus Inversus
GJB2 (Cx26), GJB6 (Cx30)
AR
Congenital Hearing Loss – Connexin 26 and 30
HPS1, AP3B1, HPS3,4,5,6,7and 8, HPS9
AR
Hermansky-Pudlak Syndrome
KCNQ1 and KCNE1
AR (Heterozygotes at risk for AD long QT a.k.a. Romano Ward syndrome)
Jervell and Lange-Nielson Syndrome
MTND1, MTND4, MTND6
Mitochondrial
Lever Hereditary Optic Neuropathy
SLC26A4 most common, FOX11, KCNJ10 in rare cases
AR
Pendred Syndrome
MYO7A, USH2A + multiple other genes
AR
Usher Syndrome
PAX3
AD
Waardenburg Syndrome
HMBS
AD
Acute Intermittent Porphyria
HBA1, HBA2
AR - If parents Alpha Thal trait, risk for HbH disease if one parent’s mutations are in cis, at risk for HB Bart if both parents in cis
Alpha Thalassemia
HBB
AR
Beta-Thalassemia
F5
AD (moderately inc. risk VTE)
AR (significantly inc .risk VTE)
Factor V Leiden Thombophilia
F8
XLR
Hemophilia A
F9
XLR
Hemophilia B
HFE
AR (penetrance is low, a large fraction of homozygotes never develop symptoms).
HFE-Associated Hereditary Hemochromatosis
BTK
XLR
X-Linked Agammaglobulinemia (Bruton’s Agammaglobulinemia)
MEFV
AR
Familial Mediterranean Fever
FGD1
XLR (some AR, AD cases reported)
Aarskog Syndrome
POR
AR
Antley-Bixler Syndrome
BBS1, BBS10
AR (though 10% BBS thought to be tri-allelic)
Bardet-Biedl Syndrome
EYA1, SIX1, SIX5
AD
Branchi-Oto-Renal Snydrome
CHD7
AD
CHARGE Syndrome
RPS6KA3
XLD
Coffin-Lowry Syndrome
NIPBL, SMC1A, SMC3, HDAC8, RAD21
AD (NIPBL and SMC3)
XLR (SMC1L1)
Cornelia de Lange Syndrome
5p Minus Syndrome
RPS14?, microRNA 145 and 146a?
12% due to unequal segregation of a translocation or recombination involving a pericentric inversion in one of the parents, 85% sporadic de novo deletions (80% are on the paternal chromosome)
Cri-Du-Chat
Unknown
AR
Fryns Syndrome
GLI3
AD
Greig Cephalipolysyndactyly
NPHP1, AHI1, CEP290, TMEM67 and others (19 genes)
AR (19 genes with rare-4% prevalence)
Joubert Syndrome
KMT2D (66%), KDM6A
AD, XLD
Kabuki Syndrome
Unknown
Monosomy 1p36
Paternally expressed genes within the imprinted locus on 15q11-13 (SNURF-SNRPN, MKRN3, MAGEL2, and NDN)
Autosomal, expressed from paternal Ch 15
3-5 Mb deletion of 15q11.2-q13 (~70%), matUPD (15%), PWS imprinting center defect (1-2%)
Prader-Willi Syndrome
CREBBP, EP300
AD
Rubenstein-Taybi Syndrome
RAI1
17p11.2 deletion (~90%) RAI1 sequencing (5-10%)
AD (sporadic unless secondary to a parental balanced translocation)
Smith-Magenis Syndrome
69,XXY>69,XXX (69,XYY very rare)
Sporadic without inc risk of recurrence
Triploidy
75% are due to maternal nondysjunction
20% to a translocation
5% to mosaicism.
Trisomy 13, Patau Syndrome
Less than 1% due to a translocation
Maternal nondysjunction (90%), mosaicism (10%)
Trisomy 18, Edwards Syndrome
90% due to maternal meiosis nondisjunction (3⁄4 MI error, 1⁄4 MII error)
Trisomy 21, Down Syndrome
unknown (HOXD13 21 bp deletions: 1 case report), FGF8?, PTF1A?
Isolated inheritance
VACTERL (VATER) Syndrome
4p deletion
Critical region includes two genes, WHSC1 and WHSC2 of unknown significance
87% de novo, 13% due to unbalanced translocation from a balanced parent
Wolf-Hirschorn Syndrome
ABCD1
XLR
X-Linked Adrenoleukodystrophy
PSEN1, APP, PSEN2
AD
Early Onset Familial Alzheimer Disease
UBE3A
4-6 Mb del (65-75%) UBE3A mutation (11%) Imprinting defect (2.5%) Unbal chrom transloc (<1%) Pat UPD 15 (<1%) Del of imprinting center (0.5%)
Angelman Syndrome
NOTCH3
AD
CADASIL
ASPA
AR
Canavan Disease
IKBKAP
AR
Familial Dysautonomia
FMR1
X-linked Triple Repeat, CGG
Fragile X
HD
AD
Huntington Disease
GALC
AR
Krabbe Disease
NF1
AD
Neurofibromatosis Type I
Multiple, main gene PARK2
AD, AR, multifactorial
Parkinson Disease
MECP2
XLD
Rett Syndrome
ATP7B
AR
Wilson Disease
SOD1 (rare: SETX, VAPB, BSCL2, VCP, ALS2, SPG20, others)
AD (AR ALS2 and SPG20)
Amyotrophic Lateral Sclerosis
CMT1: Abnormal myelin, AD, 50% of all CMT, PMP22 (17p11.2), MPZ (1q22), LITAF (16p13.1-p12.3), EGR2 (10q21.1-q22.1), NEFL (8p21)
CMT2: Axonopathy, AD, 20-40% of all CMT, KIF1B and MFN2 (1p36.2), RAB7 (3q21), LMNA (1q21.2), GARS (7p15), NEFL (8p21), HSPB1 (7q), MPZ (1q22), GDAP1 (8q12-q21.1)
CMT Intermediate Form: Combination of myelinopathy and axonopathy, AD, rare cause of CMT, DNM2 (19p12-p13.2), YARS (1p34-p35)
CMT 4: Either myelinopathy or axonopathy, AR, rare cause of CMT, GDAP1 (8q13-q21.1), MTMR2 (11q22), CMT4B2 (11p15), SH3TC2 (5q32), NDRG1 (8q24.3), EGR2 (10q21.1-q22.1), PRX (19q13.1- q13.2
CMTX: Axonopathy with secondary myelin changes, XLD, 10-20% of all CMT, GJB1 (Xq13.1).
Charcot Marie Tooth Disease
DMD
XLR
Duchenne and Becker Muscular Dystrophy
FRDA
AR
Friedrich Ataxia
PMP22
AD
Hereditary Neuropathy with Liability to Pressure Palsies
CAPN3, FKRP, LMNA, SGCA, SGCB, SGCD, SGCG, DYSF
Most AR, some AD
Limb-Girdle Muscular Dystrophy
DMPK
AD
Myotonic Dystrophy Type 1
ACTA1, NEB, TNNT1, TPM2, TPM3
RARE: CFL2, KBTBD13, KHLH40, KHLH41
AR or AD
Nemaline MyopathySpinal Muscular Atrophy
(Fukuyama (FCMD), Muscle‐Eye‐Brain (MEB), Walker‐Warburg (WWS), Congenital Muscular Dystrophy Type 1D (MDC1D) Responsible gene (protein, cytogenetic locus): FCMD; FCMD (Fukutin, 9q31); MEB: POMGNT1 (protein O‐ mannosidase beta‐1,2‐N‐acetylglucosaminyltransferase, 1p34‐p33); WWS: POMT1 and POMT2 (Protein O‐ mannosyltransferase 1 and 2, 9q34.1, and 14q24.3); MDC1D (LARGE, glycosyltransferase‐like protein LARGE, 22q12.3‐q13.1
Syndromic Congenital Muscular Dystrophy
HEXA
Follow enzyme testing with DNA testing (some with a positive enzyme assay have a pseudodeficiency allele that does not cause Tay Sachs). HEXA 6 common mutation panel: 92% of Ashkenazi Jewish
AR
Tay-Sachs Disease
BRCA1 and BRCA2
AD
BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
APC
AD (15-30% new mutation)
Familial Adenomatous Polyposis
MLH1 (3p21.3, DNA mismatch repair protein MLH1)
MSH2 (2p22-p21, DNA mismatch repair protein Msh2)
MSH6 (2p16, DNA mismatch repair protein MSH6)
PMS2 (7p22, PMS1 protein homolog 2)
AD
Hereditary Non-Polyposis Colon Cancer (Lynch Syndrome)
TP53
AD
Li-Fraumeni Syndrome
MEN1
AD
MEN Type 1 (Multiple Endocrine Neoplasia Type 1)
RET
Exon 10 and 11 (95% MEN2A), Exon 16 (95% MEN2B)
AD
MEN Type 2
NF2
AD
Neurofibromatosis Type 2
PTEN
AD
PTEN Hamartoma Tumor Syndrome
TSC1 and TSC2
AD (2/3 de novo)
Tuberous Sclerosis Complex
VHL
AD
Von Hippel-Lindau Syndrome
XPA, XPC, ERCC2, POLH
AR
Xeroderma Pgimentosum
Imprinting of 11p15.5
CDKN1C, H19, KCNQ1OT1
AD (15%)
Beckwith-Wiedemann Syndrome
NSD1
5q35 microdeletion including NSD1: ~15% (70% in Japanese).
NSD1 sequencing: 27-93% (12% in Japanese)
AD
Sotos Syndrome
APTX, SETX
AR
Ataxia with Oculomotor Apraxia Type 1 and Type 2
ERCC6 (75%), ERCC8 (25%)
AR
Cockayne Syndrome
LMNA
AD (all de novo, paternal age effect)
Hutchinson-Gilford Progeria Syndrome
SERPINA1
AR
Alpha-1-Antitrypsin Deficiency
CFTR
AR
CFTR-Related Disorders
XL: COL4A5 (80-100%)
AR: COL4A3 and COL4A4
AD: COL4A3 and COL4A4
Alport Syndrome and Thin BM Nephropathy
PKD1, PKD2 and PKHD1
AD (PKD1, PKD2)
AR (PKHD1)
Polycystic Kidney Disease
FGFR3
98% FGFR3 G1138A; ~1% FGFR3 G1138C
AD, 80% de novo
Achondroplasia
RUNX2
Microdeletions (60-70%)
AD
Cleidocranial Dysplasia
SLC26A2
AR
Diastrophic Dysplasia
FGFR1, FGFR2, FGFR3
FGFR-Related Craniosynostosis
EXT1, EXT2
AD
Hereditary Multiple Osteochondromas Syndrome
FGFR3
N540K (C1620A) (49%)
N540K (C1620G) (21%).
Exon 9, 10, 13, or 15 sequencing (80%)
AD
Hypochondroplasia
COL1A1 and COL1A2
AD and rare AR
Osteogenesis Imperfecta
TWIST1
AD
Saethre-Chotzen Syndrome
SMN1, SMN2
AR
Spinal Muscular Atrophy
CAG Triplet Repeats
Huntington Disease
Kayser-Fleisher ring
Wilson Disease
GAA Triplet Repeat
Friedrich Ataxia
FGFR1 sequencing
5% Pfeiffer 1
FGFR2 sequencing
100% Crouzon, Jackson- Weiss, Apert, Pfeiffer 2 and 3, and FGFR2-related isolated coronal synostosis
FGFR3 sequencing
100% Crouzon with Acanthosis Nigricans
FGFR3 targeted mutation analysis
100% Muenke
PAFAH1B1
Miller-Dieker
Heterozygous deletion of chromosome 22q13.3 with involvement of at least part of SHANK3
Phelan-McDermid Syndrome
STK11
AD
Peutz-Jeghers syndrome
FGFR3 pathogenic variant c.749C>G (p.Pro250Arg)
Muenke Syndrome
SALL1
Townes-Brocks Syndrome
TCOF1 - AD: 63-93%
POLR1D - AD/AR: 6%
POLR1C - AR: 1.2%
Treacher-Collins Syndrome
NBN
AR
Nijmegen Breakage Disorder
ZEB2 (also known as ZFHX1B or SIP-1)
Mowat Wilson