123 Syndromes and their Gene/Inheritance Flashcards by Rama Kastury

Deletion on 22q11.2 (3-mB del most common)
Gene: TBX1

AD, 93% de novo

22q11 Deletion Syndrome

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JAG1, NOTCH2

Alagille Syndrome

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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

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BRAF, MAP2K1, MAP2K2, KRAS

Cardio-Facio-Cutaneous Syndrome

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HRAS

Costello Syndrome

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ACVRL1, ENG, GDF2, SMAD4

Hereditary Hemorrhagic Telangiectasia

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TBX5, SALL4 (related disorder)

Hold-Oram Syndrome

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PTPN11, RAF1, BRAF, MAP2K1

Noonan Syndrome w/Multiple Lentigines (NS-ML, formerly known as LEOPARD Syndrome)

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PTPN11, SOS1, KRAS, RAF1, NRAS, CBL, SHOC2, BRAF, RIT1, SOS2, MAP2K1

Noonan Syndrome

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7q11.23 Deletion
Contiguous gene deletion syndrome, ELN in the critical region

AD most de novo

William Syndrome

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ATM

AR (carriers have increased risk of breast, colon and pancreatic)

Ataxia-Telengiectasia

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BLM

AR (1/100 carrier freq in Ashkenazi Jewish)

Bloom Syndrome

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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

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FBN2

Congenital Contractural Arachnodactyly (Beals Syndrome)

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COL5A1 and COL5A2

EDS Classic Type (Type I and II)

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Unknown Gene

EDS Hypermobility Type (Type III)

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COL3A1

EDS Vascular Type (Type IV)

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PLOD1

EDS Kyphoscoliotic Type (Type VI)

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TGFBR1, TGFBR2, SMAD3, TGFB2

Loeys-Dietz Syndrome

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FBN1

Marfan Syndrome

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GJB6

Hidrotic Ectodermal Dysplasia 2

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EDA, EDAR, EDARADD

XL (EDA:95%), AD or AR (5%)

Hypohidrotic Ectodermal Dysplasia

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IKBKG (aka NEMO)

XLD (most male fetuses miscarry)

Incontinentia Pigmenti

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TYR (OCA1), OCA2, TRYP1, SLC45A2, GPR143 (Ocular)

AR, XLR (GPR143)

Oculocutaneous Albinism

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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

123 Syndromes and their Gene/Inheritance Flashcards

(138 cards)