Glossary

A2BP1 ataxin 2-binding 1 (605104); 16p13 ABAT 4-(gamma)-aminobutyrate transferase (137150); 16p13.3 ABCA5 ATP-binding cassette, subfamily A, member 5 (612503); 17q24.3 ABCD1 ATP-binding cassette, subfamily D, member 1 (300371):Xq28 ABR active BCR-related (600365); 17p13.3 ACR acrosin (102480); 22q13.33 ACTB actin, beta (102630); 7p22.1 ADHD attention deficit hyperactivity disorder—three separate conditions ADD, ADHD, HD that manifest as poor focus with or without uncontrolled, inap- propriately busy behavior, diagnosed by observation and quantitative scores from parent and teacher questionnaires ADSL adenylosuccinate lyase (608222); 22q13.1 AGL amylo-1,6-glucosidase (610860); 1p21.2 AGO1 (EIF2C1), AGO3 (EIF2C3) argonaute 1 (EIF2C1, eukaryotic translation initiation factor 2C, subunit 1 (606228); 1p34.3, argonaute 3 (factor 2C, subunit 3—607355):1p34.3 AKAP8, AKAP8L A-kinase anchor protein (604692); 19p13.12, A-kinase anchor protein 8-like (609475); 19p13.12 ALG6 S. cerevisiae homologue of, mutations cause congenital disorder of glyco- sylation (604566); 1p31.3 Alopecia absence of hair ALX4 aristaless-like 4, mouse homolog of (605420); 11p11.2

As elsewhere in this book, 6-digit numbers in parentheses direct the reader to gene or disease descriptions in the Online Mendelian Disease in Man database (www.omim.org)

© Springer Nature Singapore Pte Ltd. 2017 461 H.E. Wyandt et al., Variation: Heteromorphism, Polymorphism and Pathogenesis, DOI 10.1007/978-981-10-3035-2 462 Glossary

GRIA1 glutamate receptor, ionotropic, AMP1 (138248); 5q33.2 ANKRD11 ankyrin repeat domain-containing protein 11 (611192); 16q24.3 Anomaly deviation from the expected or average type in structure, form and/or function which is interpreted as abnormal APBA2 amyloid beta A4 precursor protein-binding, family A (602712); 15q13.1 APC adenomatous polyposis coli (611731); 5q21q22 AQP4 4; 18q11.2q12.1 Arachnodactyly long (spider) fingers ARFRP1 ADP-ribosylation factor-related protein 1 (604699); 20q13.3 ARHGAP4 rho GTPase-activating protein 4 (300023); Xq28 ARHGEF7 rho guanine nucleotide exchange factor 7 (605477); 13q34 ARID1B AT-rich interaction domain-containing protein 1B (614556); 6q25.3 ARRDC3 arrestin domain-containing 3 (612464); 5q14.3 ARSE arylsulfatase E (300180); Xp22 ARSK arylsulfatase K (610011); 5q13 ARX aristaless-related , X-linked (300382); Xp22.13 Association Groups of anomalies that occur together more often than by chance, lacking hierarchical frequencies and characteristic facial appearance of malfor- mation syndromes ASXL1 additional sex combs-like 1 (612990); 20q11.21 AUTS14B susceptibility 14B (614671) Ataxia abnormally coordinated movements including clumsy gait as if intoxicated ATP2C2 ATPase, Ca(2+)-transporting, type 2C, member 2 (613082); 16q24.1 ATR ataxia-telangiectasia and RAD3-related (601215): 3q23 Auditory processing disorder normal hearing with delay in interpreting language Autism, autism spectrum disorder triad of poor socialization, poor communi- cation, and restricted interests/obsessive focus AVPR1A, AVPR2 arginine vasopressin receptor 1A (600821); 12q14.2, receptor 2 (300538); Xq28 B3GALTL beta-glucosyltransferase (610308); 13q12.3 BCAP1 B-cell receptor-associated protein 31 (300398); Xq28 BCL11A B-cell CLL/lymphoma 11A(606557); 2p16.1 Glossary 463

BDNF brain-derived neurotropic factor (115505); 11p13 BHLHA9 basic helix-loop-helix family, member A9 (615416): 17p13.3 Bicornuate, didelphic uterus uterus divided into two upper lobes, often with septum Bifid uvula bifurcation of midline fleshy lobule behind palate Bitemporal narrowing or hollowing concavity at temples when viewed frontally, often seen with severe hypotonia Blepharophimosis increased flesh around eyes making the palpebral fissures look narrow BMP2 bone morphogenetic protein 2 (112261); 20p12.3 BMPR1A bone morphogenetic protein receptor, type 1A (601299); 10q23.2 Bone age, delayed or advanced Age estimated from skeletal x-rays based on schedule of bone epiphysis closure, behind or ahead of chronologic age Brachycephaly flat occiput, opposite of dolichocephaly/scaphocephaly Brachydactyly fingers drastically shortened BRCA2 breast-ovarian cancer gene 2 (600185); 13q13.1 Broad forehead wide forehead, different from prominent forehead that bows frontally (frontal bossing) BSX brain-specific homeobox, mouse homologue of (611074); 11q24.1 C2ORF34 (CAMKMT) open reading frame (calmodulin lysine N-methyltransferase–609559); 2p21 C5ORF36 (KIAA0825) open reading frame 36 (not listed); 5q14— www..org/cgi-bin/carddisp.pl?gene=KIAA0825&keywords=C5orf36 C6orf70 (ERMARD) open reading frame (endoplasmic reticulum membrane-associated RNA degradation protein—615532); 6q27 CACNA1C , voltage-dependent, L type, alpha-1C subunit (114205); 12p13.3 CADPS2 calcium-dependent activator protein for secretion 2 (609978); 7q31.3 CALR3 calreticulin 3 (611414)—calcium-binding chaperone localized mainly in endoplasmic reticulum; 19p13.11 Camptodactyly finger bending forward (contracted); claw hand when all contracted CAST calpastatin isoform h (114090)—endogenous calpain (calcium-dependent cysteine protease inhibitor); 5q15 464 Glossary

Cataract, corneal opacity respective clouding of eye lens or cornea (surface of eye) CC2D1A coiled-coil and C2 domains-containing protein 1A (610095): 19p13.12 CDH9, CDH10 cadherin 9 (609974); 5p14.1, cadherin 10 (604555); 5p15.1/.2— cadherins are integral membrane that medicate Ca-dependent cell adhesion CDKL5 cyclin-dependent kinase-like 5 (300203); Xp22.13 CDKN1C cyclin-dependent kinase inhibitor 1C gene (600856); 11p14 CENPL centromeric protein L (611503)—a protein essential for proper kineto- chore function and mitotic progression; 1q25.1 CENTG2 (AGAP1) centaurin, gamma-2 (ARF GTPase-activating protein with GTPase domain—608651)—member of GTPase-activating protein family involved in membrane traffic and actin cytoskeleton dynamics; 2q37.3 Cervical sinuses fleshy openings in neck, remnants of the branchial grooves CETN3 centrin 3 centrosomic protein with 4 calcium-binding domains (602907); 5q14.3—centrins are members of a calcium-binding EF-hand protein super- family present in the centromeres of may eucaryotes CFTR cystic fibrosis transmembrane conductance regulator (602421); 7q31.2— encodes an ATP-binding cassette (ABC) transporter that functions as a , mutated in cystic fibrosis CHAT choline acetyltransferase (118490); 10q11.23—biosynthetic enzyme for acetylcholine in central/peripheral nervous system CHD7, CHD8 chromodomain helicase DNA binding protein 7 (608892); 8q12.2, protein 8 (610528); 14q11.2 CHL1 (L1CAM2) cell-adhesion molecule L1-like (L1 cell adhesion molecule 2— 607417); 3p26.3 Choanal atresia or stenosis absence or narrowing of the upper bony nasal passages CHRM3 acetylcholine receptor, muscarinic, 3 (118494); 1q43 CHRNA4, CHRNA7 cholinergic receptor, neuronal nicotinic, alpha polypeptide 4 (118504); 20q13.3, polypeptide 7 (118511); 15q14 Claw hand bending forward or camptodactyly of all fingers and Cleft lip/palate congenital failure of the upper lip or upper mouth (soft or hard palate) to fuse—cleft lip, cleft palate, or both may occur; a posterior midline U-shaped cleft of the soft palate occurs with Pierre Robin sequence because the small jaw pushes the tongue upward and interferes with palatal fusion Glossary 465

CLIC2 chloride intracellular chloride channel 2 (300138); Xq28 Clinodactyly lateral curving of a digit as opposed to the forward curve (contrac- ture) of camptodactyly CLPTM1L (CRR9) CLPTM1-like protein (cisplatin resistance-related protein 9 (612585); 5p15.33 CMIP C-MAF-inducing protein (610112); 16q23.2/.3—MAF is the avian mus- culoaponeurotic fibrosarcoma oncogene homolog CNTN3, CNTN4 contactin 3 (601325); 3p12.3, contactin 4 (607280); 3p26.3/.2— contactins are axon-associated cell adhesion molecular of the IG superfamily that play important roles in sculpting neural networks CNTNAP2 contactin-associated protein-like 2 (604569); 7q35q36 Coarse facies increased subcutaneous tissue of the face leading to a coarsened appearance Coloboma cleft of the iris that may extend to the retina, always inferior due to lack of eye cup fusion COMT catechol-o-methyltransferase (116790; 22q11.21)—the enzyme most involved in degradation of catecholamines Cortical dysplasia abnormal development of the outer layer of the brain (cortex), often detected as reduced cortical area by head MRI study COX7C cytochrome c oxidase subunit 7C precursor (603774); 5q14.3– nuclear-encoded component of the cytochrome c oxidase complex within mitochondria Craniosynostosis premature fusion of the cranial sutures that allow brain expan- sion during childhood growth CRK V-CRK avian sarcoma virus CT10 oncogene homolog (164762); 17p13.3 Cryptorchidism undescended testes, often accompanied by inguinal hernia and small scrotum CSMD3 cub and sushi multiple domains 3 (608399); 8q23.3—CUB indicates Complement C1r-U UEGF-bone morphogenetic protein BMP1, a domain in proteins with many functions ranging from complement activation, hemostasis or neural development/signal transduction; sushi is a complement control module CTNNA2, CTNND2 catenin, alpha-2 (114025); 2p12, catenin, delta-2 (604275); 5p15.2—catenins anchor cadherins to cell membranes Cupid’s bow lip enhanced curvature of the upper lip in the shape of a handle-bar mustache 466 Glossary

Cutis aplasia area lacking skin, initially fleshy, then white scar-like, often a cir- cumscribed oval on the scalp CUX2, CUTL2 cut-like 2 (610648); 12q23.13—protein similar to Drosophila cut and mouse cux2 with homeodomain CYFIP1 cytoplasmic FMRP-interacting protein 1 (606322); 15q11.2—part of a highly conserved protein family that binds to the fragile X mental retardation protein (FMRP) CYP2C19 cytochrome P450, subfamily IIC, polypeptide 19 (124020);10q23.33 Cytochrome P450 family of proteins abundant in liver that function to inactivate chemicals and many medications DAX1 (NROB1) DSS-AHC critical region on the 1, gene 1 (also nuclear receptor subfamily 0, group B, member 1; Xp21.2 DBX2 developing brain homeobox 2 (not listed);12q12—www.genecards.org/cgi- bin/carddisp.pl?gene=DBX2 Developmental field defect anomalies deriving from a common anlage or region of the early embryo, respresenting a stereotypic response to different insults DIA1 (C3ORF58) deleted in autism 1 ( open reading frame– 612200); 3q24 DISC1 disrupted in 1 (605210); 1q42.2—cloned from translocation breakpoint in patient with schizophrenia, expressed in embryonic brain and interacts with proteins of the centrosome and cytoskeleton DLG1 discs large, Drosophila, homolog of 1(601104); 3q29—a tumor suppressor in the fly, regulating epithelial cell tight junctions DLK1 delta, Drosophila, homolog-like 1 (176290); 14q32.2—epidermal growth factor repeat-containing transmembrane protein, cleaved to activate integrin DLX1, DLX2 distal-less homeobox 1 (600029); 2q31.1, distal-less homeobox 2 (126255); 2q31.1—the DLX homeobox-containing transcription factor family are essential for producing GABAergic neurons during embryogenesis DLX5, DLX6 distal-less homeobox 5 (600028);7q21.3, distal-less homeobox 6 (600030); 7q21.3 DMD dystrophin, the gene mutated in Duchenne and Becker muscular dystro- phies; 22p21.3/.2 DNAJC6 DNAJ/HSP40 homolog, subfamily C, member 6 (068375): 1p31.3— encodes auxilin, a neuronal protein involved in clathrin-dependent recycling of synaptic vesicles DNM3 dynamin 3 (611445); 1q24.3—involved in actin-dependent membrane processes such as membrane budding Glossary 467

DOCK8 dedicator of cytokinesis 8; 9p24.3—organizes filamentous actin and can produce vesicular structures with transfection Dolichocephaly, scaphocephaly prominent occiput, often seen in prematurity and dramatic with synostosis of the sagittal suture DPYD dihydropyrimidine dehydrogenase (612779): 1p21.3—the initial and rate-limiting step in pyrimidine base catabolism DSEL dermatan sulfate epimerase-like (611125); 18q22.1 DSS1 deleted in split-hand/split-foot 1 region (601285); 7q21.3—found based on association of mutations with ectrodactyly DUSP22 dual-specificity phosphatase 22 (616778); 6p25—mitogen-activated protein kinase phosphatase DYRK1A dual-specificity tyrosine -regulated kinase 1A (600855); 21q22 Dysmorphic abnormal shape due to dysmorphogenesis, most often used to describe an unusual facial appearance. Facial dysmorphology can be described more specifically in terms of minor anomalies like prominent forehead, epi- canthal folds, up- or down-slanting palpebral fissures, or micrognathia Dysphagia swallowing difficulty, usually due to low muscle tone in children with motor delays and disabilities Ears, cupped overturned helices (borders) of the outer ear or pinna, giving a cupped appearance Ears, low-set occurs when the top of the ear (superior helix of the pinna is below a horizontal line extended from the eye corners (glasses would slant downwards due to the low-set ears) Ears, over-folded helices The outer border of the pinna (external ear) is folded, giving the ear a cupped appearance Ears, posterior rotation or posteriorly rotated The superior-inferior axis of the external ear, usually parallel with the face is tilted back toward the occiput (this and low-set ears reflect abnormal ear formation and ascent from the branchial (pharyngeal) arches Ears, simplified absence of structure (inner helix, concha, tragus) inside the external ear (pinna) EB2 (MAPRE2) adenomatous polyposis coli binding protein EB2 (- associated protein, RP/EB family member 2—(605789);18q12,1/.2—interacts with , mitotic spindles, and the APC gene (611731) Ectodermal dysplasia abnormal morphogenesis of structures derived from the embryonic ectoderm (hair, teeth, nails, sweat glands), present in over 100 genetic disorders 468 Glossary

Ectrodactyly cleft hand or foot with missing middle digits (also split-hand or split-foot) EDA1 ectodysplasin A1 isoform (300451); Xq13.1—causes X-linked hypohy- drotic ectodermal dysplasia (XHED) EHMT1 euchromatic histone methyltransferase-1 gene (607001); 9q34.3 EIF4E eucaryotic translation initiation factor 4E (133440); 4q23 ELP4 elongator acetyltransferase complex, subunit 4 (606985); 11p13 EMILIN2 elastin microfibril interfacer 2 (608928); 18p11.32–triggers apoptosis (cell death) of cell lines, expressed in the skin EN2 engrailed 2 (131310); 7q36.3—regulates cerebellar and olfactory neurons in mice EPC2 of polycomb, Drosphila, homolog of, 2 (611000); 2q23.1—a histone acetyltransferase Epicanthal folds skin folds that cover the inner eye corners (canthi) Epilepsy seizure disorder that varies from grand mal tonic-clonic to various partial epilepsies that can include absence (staring) or unusual movements Epiphyses, cone-shaped abnormal shape of epiphyses with increased density on x-ray, associated with various skeletal dysplasias EPS15L epidermal growth factor receptor pathway substrate 15-like 1 (not listed); 19p13.11—http://www.genecards.org/cgi-bin/carddisp.pl?gene=EPS15L1 ERC1 ELKS/RAB6-interacting (not listed); 12p13.3—member of RIM-binding protein family, active zone proteins that regulate neurotransmitter release— http://www.genecards.org/cgi-bin/carddisp.pl?gene=ERC1 Esotropia, exotropia deviation of the eye inward, outward, a form of strabismus EST AI858607 expressed sequence tag AI858607 (not listed); 6q22.1—expressed in brain ETS2 V-ETS avian erythroblastosis virus E26 oncogene homolog 2 (164740); 21q22.2 EXT1 exostosin glycosyltransferase 1 (608177); 8q24.11—contributes to a com- plex that catalyzes the polymerization of heparin sulfate Eye contact, poor usual penetrating gaze of infancy is absent; an early sign of autism FABP5 or FABP7 fatty acid binding protein 5 (605168); 8q21.13 or 7 (602965); 6q22.31 Glossary 469

FADD FAS-associated via death domain (602457); 11q13—a universal adapter protein that mediates apoptotic signaling of TNF receptor superfamily members FAM2C (SERF2) family with sequence similarity 2, member C (small EDRK-rich factor 2—605054); 15q15.3 FAM20C family with sequence similarity 2, member C (611061); 7p22.3 FAM36A (COX20) family with sequence similarity 36, member A (cytochrome c oxidase assembly factor—614698); 1q44 FAM53A family with sequence similarity 53, member A (not listed); 4p16.— likely role I neural development; www.genecards.org/cgi-bin/carddisp.pl?gene= FAM53A FANCC Fanconi anemia, complementation group C (613899); 9p22.32—func- tions in a core complex having E3 activity for post-translational activation FBLN7 fibulin 7 (611511); 2q13—adhesion molecule that interacts with the extracellular matrix, expressed in odontoblasts and cartilage FBN1 fibrillin 1 (134797); 15q21.1—mutations cause Marfan syndrome FBXO31 F-box only protein 231 (609102); 16q24.2—acts as a protein-ubiquitin ligase FGF3 fibroblast growth factor 3 (164950); 11q13.3 FGFR3 fibroblast growth factor receptor 3 (134934); 4p16.3—mutations cause achondroplasia, hypochondroplasia, or thanatophoric dysplasia FHIT fragile histidine triad gene, fragile site (601153); 3p14.2 FLNA filamin A (300017); Xq28—patterns the actin cytoskeleton, interacting with integrins and transmembrane receptor complexes to guide cell shape and migration FMN2 formin 2 (606373); 1q43—formin domain proteins have roles in cytoskeletal organization and cell polarity FMR1 fragile X mental retardation 1 (309550); Xq27.3 FMR2 fragile site, folic acid type, rare, FRAXE (300806); Xq28 Forehead, receding or sloping hypoplasia of the upper forehead often associated with microcephaly FOXC1, FOXC2, FOXD3, FOXF1, FOXF2, FOXK2, FOXL2, FOXP2 fork- head box C1 (601090); 6p25.3, forkhead box C2 (602402); 16q24.1 forkhead box D3 (611539); 1p31.3, forkhead box F1 (603252); 16q24.1, forkhead box F2 (603250); 6p25.3, forkhead box K2 (147685); 17q25.3, forkhead box L2 470 Glossary

(605597); 3q22.3, forkhead box P2 (605317); 7q31.1—transcription factors with homology to the fly forkhead gene Frontal bossing prominent forehead with forward bulge Frontal hair upsweep frontal hair whorl FSCN1 fascin actin-bundling protein 1; 7p22.1 FTT failure to thrive, implying failure of weight gain rather than short stature GABRA1, GABRA2, GABRA4, GABRA5 gamma-aminobutyric acid receptor, alpha-1 (137160); 5q34, alpha-2 (137140); 4p12, alpha-4 (137141); 4p12, alpha-5 (137142); 15q12 GABRB2, GABRB3, GABRG3, GABRR2 gamma-aminobutyric acid receptor, beta-2 (600232); 5q34, beta-3 (137192); 15q12, gamma 3 (600233); 15q12, rho-2 (137162); 6q15 GAD1 or GAD2 glutamic acid decarboxylase-1 (605363); 2q31.1 or glutamic acid decarboxylase-2 (138275); 10p12.1 GADD45A growth arrest- and DNA damage-inducible gene (126335); 1p31.3 GALR1 galanin receptor 1 (600377); 18q23—receptor for galanin, an important neuromodulator present in brain, GI system, and hypothalomopituitary axis Gamma satellite DNA A repetitive DNA fraction consisting of various 220 bp monomers that are specific for and the X chromosome GAN giant axonal neuropathy 1 (256850); 16q23.2—gene mutated in children with the cognate disorder, with axon loss in the peripheral and central nervous system, kinky hair, and unique leg postures GARNL3 GTPase activation Rap/RanGap domain-like 3 (not listed); 9q33.3— http://www.genecards.org/cgi-bin/carddisp.pl?gene=GARNL3 GATA3, GATA4 GATA-binding protein-3 (131320); 10p14, GATA-binding protein-4 (600576); 8p23.1 GDF5, GDF6 growth and differentiation factor 5; 20q11.22, factor 6 (601147); 8q22.1 GDI1 GDP dissociation inhibitor 1; Xq28 GIN1 gypsy retrotransposon integrase 1 (not listed); 5q21.1—transcription factor with zinc finger and H2C2 domains Gingival hyperplasia overgrowth of the gums GJA1 (CX43) protein alpha-1 ( 43—121014); 6q22.31— are transmembrane proteins that constitute gap junction channels that connect the cytoplasm of neighboring cells Glossary 471

GK glycerol kinase (300474); Xp21.2 GLO1 glyoxylase 1 (138750); 6p21.2—a glutathione-binding protein that detox- ifies methylglyoxal produced by glycolysis GNAS (GNAS1) GNAS complex locus (guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1 (139320); 20q13.32 GNB1L guanine nucleotide-binding protein, beta-1 like (610778); 22q11.21 GPC5 glypican 5 (602446); 13q31.3—glypicans are heparin sulfate proteoglycan core proteins GPR172B (SLC52A1, RFT1) G-protein-coupled receptor (Solute carrier family 52, riboflavin transporter 1), SLC52A1 is approved gene symbol (607883); 17p13.2 GPR48, GPR54 (KISSIR), GPR98 (VLGR1) -coupled receptor 48 (606666); 11p14.1, receptor 54 (Kiss1r–604161); 19p13.3, receptor 98 (very large G-protein-coupled receptor 1); 5q14.3 GRIK1, GRIK2, GRIK3 glutamate receptors, ionotropic kainite 1 (138245); 21q21.3, glutamate receptor 2 (138244); 6q16.3, glutamate receptor 3 (138243); 1p34.3 GRIN1, GRIN2A, GRIN2B glutamate receptor, ionotropic, N-methyl-D-aspartate subunit 1 (138249); 9q34.3, subunit 2A (138253); 16p13.2, subunit 2B (138252); 12p13.1 GRIP1 glutamate receptor-interacting protein 1 (604597); 12q14.3 GRK1 G protein-coupled receptor kinase 1 (180381;13q34 GTPBP5 GTP-binding protein 5 (610919); 20q13.33 H19 imprinted maternally expressed noncoding transcript (103280); 11p15.5 Hammer toe flexed large toe due to contracture HDAC4 histone deacetylase 4 (605314); 2q37.3 Hemihypertrophy asymmetric halves of the body, one side larger; may have crossed hemihypertrophy where face is larger opposite to trunk and limbs Hemiplegia weakness of one side of body Heterotopia aberrant tissue in circumscribed brain regions Hip dislocation femur out of acetabulum, often congenital, detected by a char- acteristic “click” or “clunk” with hip extension Hirschsprung anomaly narrowing of lower colon segment due to absent ganglion, causing enlarged megacolon proximal to denervated area Hirsutism increased body hair 472 Glossary

HMGA1 high mobility group AT-hook 1 (600701); 6p21.31—non-histone protein that contains and DNA-binding motif (AT-hook) that binds to binds to AT-rich promoter and enhancer regions HMX2, HMX3 H6 family homeobox 2 (600647); 10q26.13, homeobox 3 (613380); 10q26.13— encoding homeobox-containing transcription fac- tors that are outside of the 4 main HOX clusters HNF1 hepatocyte nuclear factor-1-alpha gene; 12q24.31 HNRNPU heterogenous nuclear ribonucleoprotein U (602869); 1q44 failure of midline forebrain (prosencephalon) development with a spectrum of findings ranging from median central incisor to cyclopia; most cases are associated with severe ID HOXA1 homeoboxA1 (142955); 7p15.2 HYDIN hydrocephalus-inducing, mouse homolog of (610812); 16q22.2 Hypertelorism increased distance between the orbits, or by facial measurements, between the irides Hypertrichosis increased hair on body Hypoplasia underdevelopment and overdevelopment of an organism, organ or tissue resulting from a decreased or increased number of cells Hypotonia low muscle tone; recognized by decreased muscle resistance to passive movement and broad-based gait; different from decreased strength (weakness) in that it reflects resting muscle tension ICR1 telomeric imprinting control region 1 (616186) 11p15.5 ID intellectual disability or decreased cognitive function, now used instead of mental retardation; developmental delay should be used until a child is 5-6 years old and language skills wil better reflects cognitive ability than motor/speech milestones IDS iduronate 2-sulfatase (300823); Xq28—enzyme deficient in mucopolysac- charidosis II, Hurler syndrome (300823) IG-DMR (DLK1) intergenic, germline-derived control element, imprinting control region that when deleted from maternal mouse will cause loss of imprinting of nearby genes (delta, Drosophila homolog-like 1, an epidermal growth factor repeat-containing transmembrane protein (176290); 14q32.2 IHH Indian hedgehog (600726); 2q35—member of the hedgehog transcription factor family IKBKG inhibitor of kappa light polypeptide gene enhance in B cells, kinase of, gamma (300248); Xq28 Glossary 473

IL1RAPL1 interleukin 1 receptor accessory protein-like 1 (300206); Xp22.2/.3 Infantile spasms severe type of epilepsy with jerking seizures (salaam seizures, myoclonic jerks) and accompanied by hypsarrhythmia on EEG Infarction Interrupted blood supply to tissues with resulting oxygen starvation and cell death INSR Insulin receptor (147670); 19p13.2 IRF6 interleukin regulatory factor 6 (607199); 1q32.2 Iris, stellate pattern star-shaped pattern of pigmented granules in iris character- istic of Williams syndrome (194050) ITGA4 or ITGB3 integrin alpha-4 (192975); 2q31.3 or integrin beta-3 (serotonin blood level trait-173470); 17q21.32 ITGB3BP integrin, beta-3, binding protein of (605494); 1p31.3 ITSN1 intersectin 1 (602442); 21q22.11—evolutionarily conserved protein that functions in clathrin-associated endocytosis IUGR intrauterine growth retardation, one cause of small-for-gestational age or SGA (low birth weight); indicates fetal growth retardation and is a characteristic of one form of postnatal small size, primordial dwarfism JAG1 jagged 1 (601920); 20p12.2—ligand of the transmembrane Notch receptor (190198) that, when bound, triggers a cascade of proteolytic, signal transduction reactions Joint contractures congenital fixation of joints in flexion or extension, caused by decreased CNS, peripheral nerve, or muscle function if intrinsic to the fetus or through deformation by decreased amniotic fluid, uterine fibroids, etc,. if extrinsic. Injury or inflammation can cause acquired, postnatal contractures Joint laxity hypermobile joints allowing increased range of motion by passive force; often seen in connective tissue dysplasias and may be difficult to differ- entiate from early hypotonia in neurologic disorders KANSL1, KANSL3; KAT8 regulatory NSL complex subunit 1 (612452); 17q21.31, subunit 3 (not listed); 9p24.3—NSL refers to fly nonspecific lethal 2, a complex that functions as a histone acetyltransferase transferase; KAT8 (609912) is lysine acetyltransferase 8, a component of the KANSL complex KAT6A lysine acetyltransferase 6A (601408); 8p11.21 KCNE1 voltage-gated, ISK-related subfamily, member 1 (176261); 21q22.12 KCNJ3, KCNJ6, KCNJ10 potassium channel, inwardly rectifying, subfamily J, member 3 (601534); 2q24.1, member 6 (600877); 21q22.13, member 10 (602208); 1q23.2 474 Glossary

KCNQ2 potassium channel, voltage-gated, KQT-like subfamily, member 2 (602235); 20q13.33 KIAA0442 Kazusa DNA Institute brain cDNA clone 0442 (607270); 7q11.22— autism susceptibility candidate 2 (AUTS2) Kilobases (kb) Unit of DNA/RNA length = 1000 bp; Megabase = 1 million bp (1 Mb) KMT2C lysine-specific methyltrtansferase 2C (606833); 7q36.1 L1CAM L1 cell adhesion molecule (308840); Xq28 LAF4 (AFF3/FRA2A) lymphoid neuclear protein related to AF4 (AF4/FMR2 family member 3/fragile site, folic acid type, rare–601464); 2q11.2—AF4, also known as ALL1-fused gene from , is fused to ALL1 (159555) in some acute leukemias; the gene is expressed in developing brain and limb buds in mice LEMD3 LEM domain-containing protein 3 (607844); 12q14—inner nuclear membrane proteins containing lamin (LEM) domains discovered as antigens eliciting auto- in a patient with collagen vascular disease (lupus, rheumatoid arthritis) Lennox-Gastaut syndrome a form of epilepsy with body stiffening, dilation of the pupils, upward deviation of the eyes, altered respiration, and loss of muscle tone with abrupt falls LEPR leptin receptor (601007): 1p31.3 Limb shortening shortening of limb upper segment (rhizomelic), middle segment (mesomelic), or distal hand/foot (acromelic) limb-segments seen in certain skeletal dyplasias (short-limb dwarfisms) Lip upper, thin thinner than average upper lip Lips, everted upturned upper lip Lische nodules brown spots in the irides analogous to café-au-lait spots of the skin typical of neurofibromatosis-1 (162200); usually require slit-lamp for visualization Lissencephaly smooth brain lacking usual gyri LOC400685 (not listed) 19q13.11—an uncharacterized gene containing zinc-finger motifs suggesting action as a transcription factor LRP5 low density lipoprotein receptor-related protein 5 (603506); 11q13.2 LRRC7 leucine-rich repeat-containing protein 7(614453): 1p31.1—a scaffold protein that forms a complex with a calcium/calmodulin-dependent protein kinase (114078) and alpha-actinin (102575), found in postsynaptic neurons Glossary 475

LRRTM1 leucine-rich repeat transmembrane protein 1 (610867); 2p12—ex- pressed in salivary glands and brain Lymphedema lymphatic leakage producing tissues engorged with lymph that “pit” to form slowly resolving hollows when pressure is applied (pitting edema) MACC1 metastasis-associated gene in colon cancer 1 (612646); 7p21.1 Macroglossia enlarged tongue often associated with respiratory obstruction; dis- tinguished from the appearance of a large tongue when protruded from the mouth because of hypotonia Macrosomia proportional overgrowth to produce a large body MAGI2 membrane-associated guanylate kinase, WW, and PDZ domains- containing, 2 (606382); 7q21.11—a synaptic scaffolding protein membrane- associated guanylate kinase that interacts with Stargazin (CACNG2, 602911), a calcium channel protein associated with epilepsy in the stargazer mouse Major anomaly anomaly with cosmetic or surgical consequences as opposed to minor or mild anomalies that produce subtle dysmorphology Malar hypoplasia hypoplasia of the cheek/maxillary regions that derive from the branchial arches Malformation primary, intrinsic abnormality of a developing structure; contrasts with deformation or disruption where extrinsic pressure or vascular breakdown alters the structure MAOA monoamine oxidase A (309850); Xp11.3 MAP1LC3B microtubule-associated protein 1, light chain 3, beta (609604); 16q24.2 MAP2 microtubule-associated protein 2 (157130); 2q34 Marfan phenotype, Marfanoid appearance tall and thin body build with long arms and legs similar to Abe Lincoln MBD3, MBD4, MBD5 methyl-CpG-binding domain protein 3 (603573); 19p13.3, protein 4 (603574); 3q21.3, protein 5 (611472); 2q23.1 MBP myelie basic protein (159430); 18q23 MCIR melanocortin 1 receptor (155555): 16q24.3 MCPH1 microcephalin 1 (607117); 8p23.1—found in patients with microcephaly, the gene contains several BRCA1 motifs and has shown rapid in primates, proposed to correlate with brain enlargment Meckel diverticulum persistence of the embryonic omphalomesenteric duct as a blind pouch off of the intestine, present in 2% of the population MECP2 methyl-CpG-binding protein 2 (30005); Xq28 476 Glossary

MEF2C MADS box transcription enhancer factor 2, polypeptide C (600662); 5q14.3—MADS is an acronym from the several genes (MCM1 from yeast, Agamous, Deficiens from plants, SRF from ), transcription factors that bind a CC(A/T)6GG DNA motif; MEF2C and other myocyte enhancer factor (MEF) genes are expressed in skeletal muscle and brain MEG3-DMR maternally expressed gene without a known reading frame (605636); 14q32.2—The MEG3 and DLK1 (176290) genes are 80 Kb apart in the mouse and have differentially methylated regions (DMR) that control imprinting MEK2 mitogen-activated protein kinase kinase 2 (601203): 19p13.3 MET MET protooncogene (164860); 7q31.2 Metopic ridging partial fusion of the metopic suture (extending from anterior fontanel to midline forehead), projecting frontally and producing a triangular shape of the head when viewed from above (trigonocephaly) Micrognathia small jaw and chin Microphthalmia small globe of the eye, often accompanied with small palpebral fissures Microretrognathia small jaw with retrusion backwards under the mouth Microtia small external ear (small pinna) Mid-face hypoplasia shallow mid-face with the nose and maxillary region appearing concave when viewed laterally Minor anomaly anomaly that causes no medical or surgical consequences but causes dysmorphology and indicates subtle developmental change: the presence of three minor anomalies confers a *90% risk for a major anomaly/birth defect MIR4304 microRNA 4304 (not annotated); 12q24.31 MIR598 microRNA 598 (not listed) 8p23.1—http://www.genecards.org/cgi-bin/ carddisp.pl?gene=MIR598 MIR124-1 microRNA 124-1 (not listed); 8p23.1—http://www.genecards.org/cgi- bin/carddisp.pl?gene=MIR124-1 MIR137 microRNA 137 (not listed); 1p21.3—http://www.genecards.org/cgi-bin/ carddisp.pl?gene=MIR137 MIR17HG micro RNA 17-92 cluster host gene (609415); 13q31.3 MIR199A2 (MIR199), MIR214 microRNAs 199A2 (610720), 214 (610721); 1q24.3—implicated in myogenesis and osteogenesis MKX Mohawk homeobox (601332); 10p12.1—member of the three loop extension (TALE) superclass of homeobox genes, expressed in male Glossary 477

gonadal ridge and testis cords along with SOX9 (608160), a critical regulator of sexual differentiation; 10p12.1p11.23 MMP14, MMP16 matrix metalloproteinase 14 (600754); 14q11.2, matrix metal- loproteinase 16 (602262); 8q21.3 Mouth, down-turned corners as described, also called (derogatively) carp-shaped mouth, often with an elevated central portion of the upper lip (tented upper lip) MT-CYB cytochrome b of complex III (516020); mitochondrial DNA MRD1 mental retardation, autosomal dominant 1, a locus encompassed by 2q23.1 microdeletion (156200) MRX21 Mental retardation, X-linked 21 (300143) MTF1 metal regulatory transcription factor-1 (600172); 1p34.3 MTHFR 5,10-methylenetetrahydrofolate reductase (607093); 1p36.22 MTM1 myotubularin (300415); Xq28 Multicystic dysplastic kidneys multiple renal cysts (cavities) interspersed with abnormal renal tissue, often associated with back-up pressure from urinary obstruction; polycystic kidneys contain smaller and more homogenous cavities produced by abnormal development Mutism complete absence of speech as opposed to delayed speech or poor pronunciation/articulation MYCN V-MYC avian myelocytomatosis viral-related oncogene, neuroblastoma- derived (146840); 2p24.3 MYT1L myelin transcription factor 1-like (613084); 2p25.3 Nares, anteverted upturned tip of nose Nasal bridge, flat or prominent hypo- or hyperplasia of the nasal bridge by subjective perception NBEA (FRA13A) neurobeachin (fragile site 13A—604889); 13q13.3—member of the A-kinase anchor protein family (602449) that targets protein kinase A (188830) to specific cellular sites NCAM2 cell adhesion molecule, neural 2 (602040); 21q21.1—neural cell adhe- sion proteins are involved in axonal migration, synapse formation and plasticity NDE1 nude, A. nidulans, homolog of, 1 (609449); 16p13.11—rat Nude was identified based on binding to Lis-1 (601545) cDNA and is involved in cerebral cortical development NEGR1 neuronal growth regulator 1 (613173); 1p31.1 478 Glossary

NELL2 NEL-like 2 (602320); 12q12—along with NELL1 (602319) has serial epidermal growth factor-like repeats similar to the chicken nel gene and is ezpressed in fetal and adult human brain NFATC2 nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2 (600490); 20q13.2 NFIA nuclear factor IA (NFIA transcription factor—600727); 1p31.1 NFIX nuclear factor I/X (164005); 19p13.2 (NHE9) SLC9A9 (sodium/hydrogen exchanger, member 9) solute carrier family 9 (608396); 3q24 NIPA1 non-imprinted gene in Prader-Willi/Angelman syndrome chromosome region 1 (608145); 15q11.2—a membrane protein receptor or transporter expressed in neural tissue NIPBL (SCC2) nipped-B-like (sister chromatid cohesion 2–608667); 5p13.2— protein binds to cohesion (606462), counteracting force of spindle microtubules and allowing to align at the mitotic spindle Nipples, accessory atavism where additional nipples appear along the mamillary line as seen in other mammals NLGN3 (AUTSX1), NLGN4 (AUTSX2), NLGNY 3 (300336–autism susceptibility to, X-linked 1—300425); Xq13, neuroligin 4 (300427, autism susceptibility to, X-linked 2—300495; Xp22.31/.32, neuroligin 4, Y-linked (400028); Yq11.221 Nose, beaked angled or humped nasal bridge Nose, bulbous tip broad end of nose NR5A1 nuclear receptor subfamily 5, group A, member 1 (184757); 9q33.3 NRN1 neuritin 1 (607409); 6p25.1—a glycerophosphoinositol (GPI)-anchored protein that binds extracellularly to regulate neural growth NRSN2 neurensin 2 (610666); 20p13—a transport vesicle protein expressed in the hippocampus and amygdaloid nucleus NRXN1 -1 (600565); 2p16.3—over 2000 may be generated by , some shown to be involved in synpatogenic activity or in clustering neurotransmitter receptors at the postsynaptic junction NSD1 nuclear receptor-binding Su-var, enhancer of Zeste, and trithorax domain protein 1 (606681); 5q35.3—has fly motifs (zeste, trithorax) and is a co-regulator of the androgen receptor/steroid receptor superfamily (313700); Su-var is a heterochromatin methyltransferase that demarcates chromosomal subdomains NTRK2 neurotropic tyrosine kinase receptor type 2 (600456); 9q21.33 Glossary 479

NUS1 nuclear undecaprenyl pyrophosphate synthase 1, S cerevisiae homolog of (610463); 6p22.1 Oligohydramnios decreased amniotic fluid, usually because of decreased fetal urine output or amniotic ruptures OMIM Online Mendelian Inheritance in Man (omim.org), internet version of the catalogue of genetic disorders assembled by Victor A. McKusick OPN1LW, OPN1MW (LCR) OPN1LW and OPN1MW genes controller of (lo- cus controle region—300824); Xq28—OPN1LW (red) and OPN1MW (green) photopigment genes are arranged in head-to tail tandem arrays with expression regulated by this LCR OPTN optineurin (602432); 10p13—encodes an adaptor protein that regulates many cellular functions including vesicular trafficking and signaling Orthostatic tachycardia elevated heart rate on standing, often indicating poor circulation to the brain with reflexive sympathetic (adrenergic) stimulation Osteoporosis decreased bone density causing weak and brittle bones, often age-associated OXTR oxytocin receptor (167055); 3p25.3 Pachygyria abnormal cortical gyration such that there are large gyral folds PAFAH1B1 (LIS1) platelet-activating factor acetylhydrolase, isoform 1B, alpha subunit (lissencephaly 1—601545); 17p13.3 Pain insensitivity decreased sensitivity to pain is often seen in children with ID PAK2 p21 protein-activated kinase 2 (605022); 3q29 Palate, high minor anomaly of the palate where it appears to have a high arch (also high-arched palate) Palmar crease, single, deep palmar crease, excessive palmar creases abnormal palm formation and/or hand flexing during embryonic development can alter the palmar crease pattern from two to one, enhance the crease to make it more apparent (deep), or produce multiple accessory (excessive) creases Palpebral fissures, up- or downslanting (USPF, DSPF) altered slant of the eye fissures from horizontal to elevated lateral borders (as in Asians) or downshifted lateral borders Parietal foramina openings in the parietal bone caused by impaired skull development PAX3, PAX6 paired box gene 3 (606597); 2q36.1, paired box gene 6 (607108); 11p13—transcription factors that contain a paired box DNA motif based on similarity to the fly paired gene 480 Glossary

PCDH10 protocadherin 10 (608286); 4q28.3 PDE4D phosphodiesterase 4D, cAMP-specific (600129); 5q11.2/.1 Pectus concave (pectus excavatum) or convex (pectus carinatum) chest Peripheral neuropathy disease of the nerves extending from ganglia to trunk or limb muscles, characterized by sharp stinging or burning pain; peripheral autonomic nerve disease may cause enhanced or decreased sensation or paras- thesias (misperceived sensations, often noxious) Peters anomaly developmental anomaly of the eye anterior segment (lens, iris, cornea) with incomplete separation of the cornea from the iris or lens, causing a cloudy cornea of various size and blurred vision PHF8 PHD finger protein 8 (300560); Xp11.22—an iron and 2-oxoglutaric acid-dependent lysine demethylase acting on histones, initially isolated from brain cDNA PHF21A PHD finger protein 21A, part of the BRAF histone deacetylase complex (608325);11p11.2 Philtrum long, flat, or prominent the midline crease from nasal columella to the upper lip is either elongated, less visible, or more pronounced (flat philtrum is often seen in fetal alcohol spectrum disorder) PIGW phosphatidylinositol glycan anchor biosynthesis class W protein (610275); 17q12 PIK3CB phosphatidylinositol 3-kinase, catalytic, beta (602925); 3q22.3 PITX1, PITX2 paired-like homeodomain transcription factor 1 (602149); 5q31.1, factor 2 (601542); 4q25 PKD2 (173910); 4q22.1—isolated from study of polycystic kidney disease type 2, it is a calcium channel and a member of the transient receptor potential (TRP) channel superfamily Plagiocephaly lop—sided head shape, often associated with wry neck (torticollis) and correctable by wearing bands or helmets during infancy PLCB1 phospholipase C, beta-1 (607120); 20p12.3 Pleiotropy Multiple traits determined by a single cause, often a gene mutation PMP22 peripheral myelin protein 22 (601097); 17p12 Polydactyly extra digit, preaxial (thumb-side) or postaxial (5th finger-side) Polyhydramnios Excess amniotic fluid due to increased maternal production or decreased fetal absorption (i.e,. fetal swallowing defects) Preauricular pits small pits in front of the upper external ear (pinna) Glossary 481

PRKCB1 protein kinase C beta-1 (176970); 16p12.2/.1 PRKG2 protein kinase, cGMP-dependent, type II (601591); 4q21.21 Prognathism enlarged or prominent jaw PRPF31 precursor mRNA-processing factor 21, S cerevsiae homolog of (606419); 19q13.42 PTCH1 patched, Drosophila homolog of (601309); 9q22.32–transmembrane protein homolog of fly Patched gene that regulates TGF-beta (190180) and Wnt (164820) transcription factors PTEN phosphatase and tensin homolog (601728); 10q23.31—a tumor suppressor phosphatase that negatively regulates the PI3K (601232)and MAPK (605069) signaling pathways Ptosis drooping of the upper eyelid producing a sleepy appearance PTPN1 protein-tyrosine phosphatase nonreceptor-type 1 (176885); 20q13.13, type 9 (600768); 15q24.2 PUF60 poly-U-binding-splicing factor, 60-KD (604819);8q24.3 PXDN peroxidasin, Drosophila, homolog of (605158); 2p25.3—an extracellular matrix-associated peroxidase Pyelectasis dilation of the renal pelvis, similar to hydronephrosis that can involve the pelvis and ureters Pyloric stenosis congenital narrowing of the pylorus (junction of stomach and intestines) that produces obstruction and projectile vomiting in the infantile period RAB11FIP5 RAB11family interacting protein 5 (605536); 2p13.2—RAB family proteins are RAS-related small GTP-binding proteins that regulate exo- and endocytotic cellular pathways RAB39B RAS-associated protein (300774); Xq28—the term ‘RAS’ derives from RAt Sarcoma viruses Harvey and Kirsten, their respective viral oncogenes (HRAS, KRAS) having DNA motifs that defined a family of RAS genes RABL2B RAB-like 2B (605413); 22q13.33 RAI1 retinoic acid induced gene (607642); 17p11.2—regulates CLOCK (601851) and other components of the circardian rhythm feedback loop RALGPS ral GEF with PH and SH3 binding motif 1 (not listed); 9q33.3—http:// www.ncbi.nlm.nih.gov/gene?cmd=retrieve&list_uids=9649; guanine nucleotide exchange factors (GEF) induce release of GDP from inactive GDP-bound RAS RAPGEF4 RAP guanine nucleotide exchange factor (606058); 2q31.1—a RAS-related GTPase expressed in brain and adrenal gland 482 Glossary

RASA1 RAS p21 protein activator 1)139150); 5q14.3—a cytoplasmic GTPase- activating protein RASGEF1B RASGEF domain family member 1B (613532); 4q21.21—a guanine nucleotide exchange factor (GEF) acting on RAS RBM8A RNA-binding motif protein 8A (605313); 1q21.1 RCAN1 regulator of calcineurin-1 (602917); 21q22.12 REEP1, REEP3 receptor expression-enhancing protein 1 (609139); 2p11.2, pro- tein 3 (609348);10q21.3—transmembrane proteins that help transport G protein-coupled receptors to cell surface membranes RELN reelin (600514); 7q22.1—in mice mutated to cause the ‘reeler’ phenotype with poor coordination Retrognathia retrusion of the jaw, usually because of abnormal development RNF8, RNF135 Ring finger protein 8 (611685); 6p21.2, protein 135 (611358); 17q11.2—RNF8 encodes a ubiquitin ligase ROPN1L rhophilin associated tail protein 1-like (611756); 5p15.2—some gene regions are homologous to those of protein kinase PRKARIA (188830) RPL15, RPS19, RPS7P5 ribosomal protein L15 (604174); 3p24.2, protein S19 (603474); 19q13.2, protein S7 pseudogene 5 (not listed);1q43-www.genecards. org/cgi-bin/carddisp.pl?gene=RPS7P5 RTL1 retroposon-like gene 5 (611896); 14q32.2—the mouse homolog Rt11 is a paternally expressed imprinted gene highly expressed in late gestation fetus and placenta RUNX1 runt-related transcription factor (151385);21q22.12—RUNX transcription factors have a Runt domain found in the fly runt gene that participates in early pattern formation RXRA alpha (180245); 9q34.2 SALL1, SALL4 Sal-like 1 (602218); 16q12.1,: Sal-like 4 (607343); 20q13.2— genes homologous to the spalt (sal) gene of the fly that specifies anterior and posterior embryonic segments SATB2 special AT-rich sequence-binding protein 2 gene (608148); 2q33.1—a nuclear matrix DNA-binding protein that regulates transcription and modeling Satellite DNA Highly repetitive DNA that was first recognized as a separate band after DNA centrifugation Schizophrenia psychosis (defined by presence of hallucinations) with flat affect that often has sudden onset in the late teen, early adulthood years Glossary 483

Sclerae whites of the eyes SCN1A , neuronal type I, alpha subunit (182389); 2q24.3 SCN7A sodium channel, voltage-gated, type VII, alspha subunit (182392); 2q24.3 SCT secretin (182099); 11p15.5 SDC2 syndecan 2 (142460); 8q22.1—a transmembrane heparin sulfate proteoglycan Self-mutilation recurrent skin-picking or biting that results in surface injury and scarring, often due to self-stimulatory or stereotypic (habitual) movements SEMA5A semaphorin 5A (609297); 5p15.31—transmembrane protein involved in axonal guidance during neural development Sequence (re birth defects) cascade of primary and secondary events that are consequences of a single primary malformation or disruption SERPINB6 serpin peptidase inhitibor, clade B (ovalbumin), member 6 (173321); 6p25.2—expressed in the cytoplasm of embryonic and adult mouse cochlear hair cells SETD1B (KMT2G), SETD5 SET domain-containing protein 1B (lysine-specific methyltransferase 2G—611055): 12q24.31, protein D5 (615743); 3q25.3 SGCB sarcoglycan-beta (600900), the gene mutated to cause limb-girdle muscular dystrophy type 2E (604286); 4q12 SH2B11 (not listed) 6p11.2—contains an adaptor protein that interacts with the insulin receptor and certain protein kinases and associates with obesity; http:// www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch= 25970 SHANK3 (PSAP2) SH3 and multiple ankyrin repeat domains 3 (proline-rich synapse-associated protein–606230); 22q13.33 Shawl scrotum scrotal sacs joined by a band across the dorsal phallus (also, saddle-bag scrotum) SHH sonic hedgehog (600725); 7q36.3—one of the transcription factor family homologous to fly hedghog Silent mutations Mutations that do not alter protein sequence or structure SIX2 sine oculis homeobox, Drosphila, homolog of, 2 (604994); 2p21—homolog of the fly sine oculis (so) gene that is expressed in the developing visual system SLC18A3 solute carrier family 18 (vesicular acetylcholine), member 3 (600336); 10q11.23 SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3 (600111); 5p13.2 484 Glossary

SLC25A12 solute carrier family 25 (mitochondrial carrier, ARALAR), member 12 (603667); 2q31.1 SLC35F1 solute carrier family 35, member F1 (not listed); 6q22.1—http:// atlasgeneticsoncology.org/Genes/GC_SLC35F1 SLC3A1 solute carrier family 3 (cystine, dibasic, and neutral amino acid trans- porter), member 1 (104614); 2p21 SLC40A1 solute carrier family 40 (iron-regulated transporter), member 1 (604653); 2q32.2 SLC4A10 solute carrier family 4 (sodium bicarbonate transporter-like),member 10 (605556); 2q24.2 SLC52A1 solute carrier family 52 (riboflavin transporter), member 1 (607883); 17p13.2 SLC6A3 solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (126455); 5p15.33 SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (182138); 17q11.2 SLC9A9 (NHE9) solute carrier family 9 (sodium/hydrogen exchanger, member 9 (608396); 3q24 SLCO5A1 solute carrier organic anion transporter family, member 5A1 (613543); 8q13.3 Sleep apnea nocturnal cessation of breathing, either obstructive (tongue retraction, increased tonsillar tissue, obesity) or central (abnormal brain signaling) Sleep disturbance failure to initiate or maintain sleep, often present in autism and autonomic disorders SMC1A, SMC2, SMC3 structural maintenance of chromosomes 1A (300040); Xp11.22, 2 (615222); 9q31.1, 3 (606062);10q25.2—proteins required for seg- regation of the chromosomes at mitosis SOX 7, SOX10, SOX11, SOX12 SRY-box 7 (612202); 8p23.1, box 10 (602229); 22q13.1, box 11 (600898); 2p25.2, box 12 (60194); 20p13—transcription fac- tors containing high mobility group (HMG) DNA-binding motifs noted in the testis-determining gene SRY (480000) Spasticity, spastic paraplegia increased muscle tone causing tight muscles and toe-walking, often seen in cerebral palsy—paraplegia refers to muscle weakness Speech apraxia apraxia has broad meaning, but generally denotes inability to carry out a skilled movement despite intact strength and sensation; speech apraxia means speech that is not coherent due to oral muscle incoordination or to inappropriate word use, the latter feature often seen in autism Glossary 485

SSBP1 single-stranded DNA-binding protein 1 (600439); 7q34—binds and sta- bilizes the single-stranded mitochondrial DNA within the D-loop during mito- chondrial DNA replication ST7 suppressor of tumorigenicity 7 (600833); 7q31.2 ST8SIA4 ST8 alpha-N-acetyl-neuraminide, alpha-2,8-sialyltransferase 4 (602547); 5q21.1—synthesizes polysialic acid that modulates neural cell adhesion mole- cule (116930) Stereotypic movements stereotypies—repeated, non-purposeful movements often seen in autism STK11, STK39 serine/threonine protein kinase 11 (602216); 19p13.3, kinase 39 (607648); 2q24.3 Stop codons codons that signal termination of the amino acid chain during translation Storage diseases metabolic disorders caused by lysosomal enzyme deficiency with accumulation of large molecules (carbohydrates, glycoproteins, glycosamino- glycans complex lipids) in tissues, producing organ failure; they are insidious disorders that produce a coarsened facies and/or visceromegaly that contrasts with the normal appearance and acute catastrophic illness of small molecule disorders like medium chain coA dehydrogenase deficiency (607008) STS Steroid sulfatase (300747); Xp22.31 STXBP1 syntaxin-binding protein 1 (602926); 9q34.11 SULF1 sulfatase 1 (610012); 8q13.2/.3 SULT4A1 sulfotransferase family 4A, member 1 (608359);22q13.31 SUPT16H suppressor of TY 16, S. Cerevisiae homolog of (605012); 14q11.2–part of the complex that facilitates chromatin transcription, DNA replication and repair Syndactyly fusion of digits, involving the bones and/or surrounding skin Synophrys joining of the eyebrows in the midline T2R3, TAS2R3 taste receptor type 2, member 3 (604868); 7q34 TAB2 TAK1 binding protein 2 (605101): 6q25.1—TAK1 abbreviates TGF-beta- activated kinase 1 TACC3 transforming, acid, coiled-coil-containing protein 3 (605303); 4p16.3 Taurodontism developmental dental anomaly where the body and pulp chamber are enlarged relative to the tooth root 486 Glossary

TBC1D24 TBC1 domain family member 24 (613577); 16p13.3—TBC (Tre2- Bub2-Cdc16) domain-containing genes encode RAB-specific GTPase-activating proteins involved in intracellular vesicle transport TBX1, TBX4 T-box 1 (602054); 22q11.21, T-box 4 (601719): 17p23.2–T-box genes encode transcription factors regulating development TCF4 transcription factor 4 (602272); 18q21.2 TECR (GPSN2) trans-2,3-enoyl-CoA reductase (glycoprotein, synaptic 2– 610057); 19p13.12—final step in microsomal very long chain fatty acid synthesis Telecanthus increased distance between the eye corners (canthi) study of abnormal development, particularly connoting influence of drugs, chemicals, and physical agents TERT telomerase reverse transcriptase (187270); 5p15.33 TFDP1 transcription factor DP1 (189903); 13q34—part of the E2F-transcription factor family that regulates promoter expression, particularly those involved in the cell cycle TGIF1 transforming growth factor-beta-induced factor (602630); 18p11.31— transcriptional regulator that belongs to the TALE (Three Amino acid Loop Extension) homeodomain family THBS2, TSP2 thrombospondin 2 (188061); 6q27–an astrocyte-secreted protein of the extracellular matrix that promotes synaptogenesis, neurite outgrowth, and cerebellar granule cell migration , proximal subjective impression that the attachment of thumbs to the hand is lower than usual, toward the wrist TMEM87B transmembrane protein 87B (not listed); 2q13–www.genecards.org/ cgi-bin/carddisp.pl?gene=TMEM87B TMPRSS6 transmembrane protease, serine 6 (609862); 22q12.3 TNKS, TNKS1 TRF1-interacting ankyrin-related ADP-ribose polymerase (tankyrase-603303); 8p23.1-regulates telomere function by inhibiting telomerase at telomere ends TP53 tumor protein 53 (191170); 17p13.1 Triangular face facial appearance created by a prominent forehead tapering to a small chin, viewed frontally Trigonocephaly protruding metopic suture (from anterior fontanel to mid- forehead), creating a triangular cranial appearance when viewed from above Glossary 487

TRIP8 (JMJD1C) thyroid hormone receptor interactor 8 (jumonji domain-containing protein 1C (604503); 10q21.3 TRPA1 transient receptor potential cation channel, subfamily A, member 1 (604775); 8q21.11 TRPS1 Zinc finger transcription factor (604386); 8q23.3 TUBB3 tubulin, beta-3 (602661); 16q24.3 Turricephaly high forehead viewed frontally due to craniosynostosis of the coronal sutures, forcing upward rather than anteroposterior skull growth TWIST1 Twist, Drosophila homolog of, 1 (601622); 7p21.1—member of the basic helix-loop-hleix (bHLH) transcriptional regulators that have homology to the gene responsible for the fly Twist mutation UBA2 ubiquitin-like modifier-activating enzyme 2 (613295); 19q13.11 UBE3A ubiquitin-protein ligase E3A; 15q11.2 Uniparental disomy Two copies of a chromosome pair in offspring derived from one parent UPF3, UPF3B UPF3 yeast, homolog of, B (300298); Xq24—component of an exon-junction complex that mediates nonsense-mediated decay of transcripts with premature termination codons VCX (VCX10R, VCX1) variably charged, X chromosome (variably charged, X chromosome with 10 repeats, variably charged X chromosome B1 (300229); Xp22.31 VCX2, VCX3A variably charged X chromosome 2 (300532); Xp22.31; variably charged X chromosome 3A (300533); Xp22.31 Velopalatine insufficiency abnormal soft palate function resulting in formula coming out the nose in infancy and speech articulation defects in childhood Vesicoureteral reflux leakage and back-flow of urine from the bladder to the ureters—can result in renal failure from pressure VKORC1 vitamin K epoxide reductase complex, subunit 1 (608547); 16p11.2 WACWW domain-containing adaptor with coiled-coil region (615049); 10p12.1— homolog of the mouse Wac protein that is located in the nucleus and includes WW domains related to RNA processing Webbed neck (pterygium colli) excess neck tissue representing a neck mass (cystic hygroma) in fetuses that regresses to a web of skin and lymphatic tissue WNK3 protein kinase, lysine-deficient (300358); Xp11.22 WNT2 wingless-type MMTV integration site family, member 2 (147870); 7q31.2 488 Glossary

WT1; WT1 gene (607102) 11p13—isolated from the 11p13 region related to Wilms tumor, encoding a zinc finger DNA-binding transcription factor involved in genitourinary development YWHAE tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon isoform (605066): 17p13.3 YY1 transcription factor YY1 (600013); 14q32—a ubiquitous transcription factor with roles in embryogenesis and cellular proliferation ZFHX1B zinc finger E box-binding homeobox 2 (605802); 2q22.3—a DNA-binding transcriptional repressor ZIC2 zinc finger protein of cerebellum 2 (603073);13q32.3 ZNF238 (ZBTB18) zinc finger protein 238 (zinc finger and BTB domain- containing protein 18—608433; 1q44 ZNF181, ZFP276 zinc finger protein181 (606741); 19q13.1, zinc finger protein 276 (608460); 16q24.3 Index

A E Applications of FISH, 177 Epigenesis, 456 Array CGH (aCGH), 235, 236 Epigenetic factors, 58 Euchromatic variants, 57, 58 B Benign, 235–238, 240, 248, 261, 266, 275, F 282, 298, 303, 317, 318, 327, 341, 352, FISH probes, types of, 176, 177, 179, 180, 182, 368, 385, 386 183 Breakthrough of the Year, 2007, 1 Fluorescence In Situ Hybridization (FISH), 14, 26–28, 175 C Fragile site, 2, 6, 145, 146 Cancer, 51–53, 146, 147 Cancer genetics, 3 G Case examples, 210, 219 , 3 Causes and mechanisms of, 146, Genes, 235, 236, 238, 309 147 Genetic testing, 203, 212–214, 218, 224, 229 Chromosome banding techniques, sequencing, 447 13, 15 Genome structure, 194 Clinical associations, 235, 248, 303 Clinical genetics, 2, 4 H CNV catalog, 248 Heteromorphism, 2, 5, 7, 13, 14, 26 CNV locations (by sequence position by chromosome banding, 64, 66, 68, 72, and chromosome band), 238 73, 75, 76, 78, 82, 93, 95, 97, 104, 109, CNV tables (by chromosome), 235, 238, 240, 113, 115, 116, 120 246 by chromosome number, 63, 72, 95, 98, Common fragile site, 145–147 104 Comparative genomic hybridization (CGH), by FISH, 75, 76, 80, 90, 104, 116, 197 118–120, 122, 127 Copy number variations (CNVs), 6, 58, 191, by special techniques, 118, 120 192, 197, 199, 235 microscopically detectable, 63 Correction of defects, 213 Heteromorphism frequencies, 40, 45 Heteromorphisms by FISH, 178 D , 1, 4, 5, 7 Developmental genetics, 211 I Disease, 145, 146 Inheritance, 420, 423, 427, 442, 443, 446, 447 DNA diagnosis, 419, 421, 423 Innocent vs criminal, 455 DNA replication, 16, 23 Instability of, 146, 147

© Springer Nature Singapore Pte Ltd. 2017 489 H.E. Wyandt et al., Human Chromosome Variation: Heteromorphism, Polymorphism and Pathogenesis, DOI 10.1007/978-981-10-3035-2 490 Index

L Precision medicine, 447 List of (by chromosome location), 147 Prenatal diagnosis, 457, 458 Pseudogenes, 57, 58 M Massive parallel (NextGen) DNA sequencing, R 5 Rare fragile sites, 146 Mechanisms, 199, 206, 223 Reproductive failure, 47, 48, 50 Methods, 191 Microarray, 3, 5, 7 S Microarrays, aCGH, 191, 195–201, 203, Satellite association, 50 205–207, 211, 210, 213–215, 218–220, 223 Satellite DNAs, 14, 26 Microduplications/deletions, 57, 58 Specialized banding techniques, 14 Mobile elements, 50 Spontaneous abortions, 48 Molecular genetics, 7 Stochastic approach, 201, 206, 207 Study Comparisons, 43 N Subtelomeric variants, 182, 185, 187 Neurobehavioral phenotypes, 424 Summary, 455 New Haven study, 40 Non-disjunction, 48, 50, 51 T Novel mutations, 424, 432, 434, 441, 443 Testing sensitivity, 455–457

P V Pathogenesis, 202, 206, 207, 209, 434, 436, Variable phenotypes, 58 438, 442, 445, 446, 451 Pathogenetic, 235, 236, 266, 275, 282, 298, W 309, 313, 322, 327, 341, 352, 362, 368, 385 Whole Exon Sequencing (WES), 2, 5, 7, Pharmacogenetics, 7, 8, 447–449, 451 8, 446 Polymorphism, 5, 6, 199, 203 Whole Genome Sequencing (WGS), 5 Population frequencies, 37, 42