Table 4.
Novel candidates
| ID | Variant | Zygosity | Observed phenotype | Justification for candidacy |
|---|---|---|---|---|
| 16-2679 | ABHD6:NM_020676:exon3:c.185A>C:p.Y62S | Hom | Fine motor delay, speech delay, intellectual disability/MR, autism spectrum disorder, autistic features, pachygyria, diffuse WM, signal changes, (younger brother) | (a) The nature of the variant (predicted deleterious, novel, within autozygome) and (b) the nature of the gene (involved in synapse function (PMID: 27114538) |
| 16W-0323 | ACY3:NM_080658:exon5:c.512C>A:p.A171D | Hom | Microcephaly, seizures, spasticity, brain atrophy | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (same family of genes as ACY2 responsible for Canavan disease) |
| 16W-0267 | ADGRB2:NM_001294336:exon3:c.21+1G>C | Het | Macrocephaly, fine motor delay, gross motor delay, speech delay, hypotonia | (a) The nature of the variant (novel and potentially truncating) and (b) data showing significant enrichment of ADGRB2 in the brain (PMID: 20367554) |
| 16N-0253 | ADGRG7:NM_032787:exon2:c.170C>A:p.T57 N | Hom | Muscle pain following exercise for few years rhabdomyolysis, asymptomatic otherwise, no muscle atrophy or hypertrophy, no tenderness, CK on last visit >15000 following exercise, power is good on examination | (a) The nature of the variant (novel, predicted to be deleterious and within autozygome) and (b) the nature of the gene (this is a G protein-coupled receptor that has been shown to be expressed in skeletal muscle as per ENSBTAG00000012140 in EBI) |
| 16W-0209 | AGTPBP1:NM_001286715:exon20:c.2908C > T:p.R970 W | Hom | Failure to thrive, Fine motor delay, gross motor delay, speech delay, intellectual disability/MR, hypotonia, brain atrophy, undescended testis, micropenis, poor vision | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (compatible (mouse model PubMed: 11884758) |
| 16W-0085 | AHNAK2:NM_138420:exon7:c.6436_6437insGG:p.L2146 fs | Hom | Dysmorphic features, mitral regurgitation, skeletal deformities | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (influences FGF1 secretion, which is known to play a role in skeletal development PMID 25560297) |
| 16W-0212 | AKAP6:NM_004274:exon4:c.1874A>T:p.Y625F | Het | ID, precocious puberty | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (pLI score of 1.00, implicated in cognitive function (PMID: 25644384), the presence of another case with ID and de novo heterozygous truncating variant (see text) |
| 16W-0156 | ASB3:NM_001201965:exon5:c.386-3T>C | Hom | Ataxia, Dystonia, Hypertonia, bilateral basal ganglia disease on MRI, brother has epilepsy | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (expressed in forebrain PMID: 18817551) |
| 16-2656 | ATXN1L:NM_001137675:exon3:c.982C > T:p.R328 W | Het | Ataxia, patient with cerebellar dysfunction beginning since age 5–6 years | (a) The nature of the variant (novel and predicted deleterious) and (b) the nature of the gene (implicated in SCA1 neuropathology PMID 17322884) |
| 16W-0243 | C17orf62:NM_001033046:exon3:c.127G>A:p.D43 N | Hom | Growth retardation/short stature, lymphadenopathy, hepatosplenomegaly, recurrent fever, anemia/neutropenia/pancytopenia, HLH rule out | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (part of the leukocyte nuclear envelope proteome PMID: 20693407) |
| 16N-0312 | CABP1:NM_001033677:exon4:c.922C>T:p.R308X | Het | Microcephaly | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (PLI 0.99, encodes a neuronal calcium‐binding protein) |
| 16W-0208 | CCDC186:NM_018017:exon2:c.610C>T:p.Q204X | Hom | Failure to thrive, fine motor delay, gross motor delay, speech delay, intellectual disability/MR, hypotonia, brain atrophy, undescended testis, micropenis, poor vision | (a) The nature of the variant (novel, predicted deleterious and within autozygome) and (b) the nature of the gene (encodes a component of dense-core vesicles (DCVs), which are secretory organelles that store and release modulatory neurotransmitters doi: http://dx.doi.org/10.1101/105668) |
| 16N-0321 | CCP110: NM_001199022:exon4:c.1355A>G:p.D452G | Het | Tetralogy of Fallot, failure to thrive, growth retardation/short stature, microcephaly, fine motor delay, gross motor delay, speech delay, intellectual disability/MR, hypotonia | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (encodes a ciliary protein and its mouse knockout shows overlapping features PMID 26965371) |
| 16W-0333 | CLSTN2:NM_022131:exon14:c.2296C > T:p.R766C | Hom | Intellectual disability, autism spectrum disorder, ADHD | (a) The nature of the variant (novel, predicted deleterious), and (b) the nature of the gene (implicated in cognition in mouse PMID: 26171716) |
| 16W-0308 | CNTN3:NM_020872:exon17:c.2309C>T:p.P770L | Hom | Microcephaly, intellectual disability/MR, learning disability, severe ADHD, mild motor delay | (a) The nature of the variant (novel and predicted deleterious), and (b) this gene has been found to be expressed in the mouse subventricular zone proliferative cells (PMID: 23914158), which would be consistent with a potential role in the primary microcephaly phenotype this patient has |
| 16W-0185 | CNTN5:NM_175566:exon15:c.1955T>G:p.I652R | Het | Fine motor delay, speech delay, intellectual disability/MR, learning disability, developmental regression, hypertonia, seizures tonic, spasticity, cerebellar atrophy, GDD, epilepsy | (a) The nature of the variant (novel and predicted deleterious) and b) the nature of the gene (%HI score of 6 and suggested role in neuronal development PMID: 26391921) |
| 16-2542 | CTNNA2:NM_001164883:exon4:c.299G>C:p.G100A | Het | Microcephaly, gross motor delay, speech delay, intellectual disability, learning disability, developmental regression, neuroregression, autistic features | (a) The nature of the variant (novel and predicted deleterious) and b) the nature of the gene (PLI of 1.00 and established role in brain based on the mouse model (PubMed: 9060409) |
| 16W-0318 | CWC22:NM_020943:exon20:c.2305_2306del:p.D769 fs | Het | Short stature, and progressive bowing of both legs. DNA analysis for ALPL gen and FGF23 gene are normal (no mutation detected). Skeletal dysplasia of unknown origin | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (required for the proper targeting of another skeletal dysplasia gene reported in this paper PMID: 24360810) |
| 16N-0300 | DMAP1:NM_019100:exon9:c.1175G>A:p.R392Q | Het | Developmental delay, dysmorphic, hypertelorism, low set ears, ear tag, long philtrum, other extremities | (a) The nature of the variant (novel, predicted deleterious), and (b) the nature of the gene (Tanaka H, Amou R, Shiraki T, Kobayashi M, Nakayama R, Okamoto H. Involvement of DMAP1 in the neural migration and differentiation in zebrafish. Neuroscience Research. 2007 Dec 31;58:S83) |
| 16W-0079 | DMKN:NM_001126057:exon5:c.850_851insCA:p.G284 fs | Hom | Ventricular septal defect, speech delay, learning disability, cleft lip/palate, skin laxity, joint laxity | (a) The nature of the variant (novel, truncating, within autozygome) and (b) the nature of the gene (appropriate expression pattern PMID: 17380110) |
| 16-2628 | DMXL1:NM_001290321:exon18:c.4256delG:p.C1419fs | Het | Global developmental delay, speech delay, hypotonia, seizure, ptosis, optic disc edema, hypoplastic left heart, congenital heart disease, right UPJ obstruction with grade v hydronephrosis and dysmorphic features. Neuro panel is negative | (a) The nature of the variant (predicted deleterious, novel) and b) the nature of the gene (PLI score of 1.00, its Drosophila ortholog KO has abnormal development PMID: 25259927, and has been proposed to play a role in the pathogenesis of 5q22.3q23.3 microdeletion syndrome PMID: 15742475) |
| 16W-0265 | DSCAM:NM_001271534:exon23:c.4132+2T>A | Hom | Growth retardation/short stature, microcephaly, fine motor delay, gross motor delay, speech delay, intellectual disability/MR, seizure | (a) Nature of the variant (novel and potentially truncating), and (b) this gene has an extensively studied role in axon development in the CNS (PubMed: 10892653) |
| 16W-0183 | DVL2:NM_004422:exon14:c.1690C > T:p.Q564X | Hom | Cardiomyopathy, short stature, ptosis, facial dysmorphism, developmental delay | (a) The nature of the variant (novel, predicted deleterious, within a run of homozygosity) and (b) the nature of the gene (compatible mouse knockout phenotype PMID: 12421720) |
| 16W-0102 | ECI1:NM_001919:exon5:c.563+1G>T | Hom | Fine motor delay, gross motor delay, speech delay, Intellectual disability/MR, learning disability, hypertonia, dysmyelinating disease | (a) The nature of the variant (novel, predicted deleterious, within a run of homozygosity) and (b) the nature of the gene (this gene encodes mitochondrial 3, 2-trans-enoyl-CoA isomerase which catalyzes the shift of the double bonds of 3-cis- and 3-trans-isomers to the 2-trans-enoyl-CoAs, which are substrates of the 2-trans-enoyl-CoA hydratase) |
| 16N-0280 | EP400:NM_015409:exon47:c.8226_8227insGCAACAG:p.Q2742 fs | Het | GDD, epilepsy and CHD | (a) The nature of the variant (novel, truncating) and (b) the nature of the gene (it has a PLI score of 1, and is a chromatin modulator (PMID: 26669263), which is a class commonly mutated in intellectual disability and congenital heart disease) |
| 16W-0213 | EPB41L5:NM_001184939:exon14:c.1178+1G>T | Het | Fine motor delay, hypertelorism of eye, panhypopituitarism, myelomeningocele, dislocated hips, scoliosis | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (implicated in the specification and differentiation of neurons PMID: 27510968) |
| 16W-0230 | FBXL22:NM_203373:exon1:c.279G>C:p.K93 N | Hom | Muscle weakness, proximal lower extremity, calf prominence, CK 5000 increase, LGMD phenotype, DMD (at MDL) negative, NGS (myopathy) at MNG lab negative | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (implicated in sarcomere physiology PMID: 22972877) |
| 16-2696 | GAP43:NM_002045:exon3:c.629-3C>T | Het | Motor neuron disease, paraparesis, spastic with upper and lower motor neuron signs | (a) The nature of the variant (predicted deleterious, novel) and (b) the nature of the gene (involved in axon regeneration (PubMed: 7859286) |
| 16W-0312 | GEMIN7:NM_001007269:exon2:c.154G>A:p.E52 K | Hom | Gross motor delay, speech delay, normal metabolic, normal MRI, hypotonia, abnormal movements, myoclonic but no seizures | (a) The nature of the variant (novel, predicted deleterious, within autozygome), and (b) the nature of the gene (implicated in motor neuron survival PMID: 12065586) |
| 16W-0320 | GIT1:NM_001085454:exon5:c.611T>A:p.I204 N | No information | (a) The nature of the variant (novel, predicted deleterious), and (b) the nature of the gene (PLI 1.00, relevant mouse phenotype PMID: 25997734) | |
| 16W-0313 | GRIK4:NM_001282470:exon19:c.2479T>G:p.F827 V | Hom | Microcephaly, developmental regression, patient niece have severe GDD, patient sister died at 3 years old with GDD | (a) The nature of the variant (novel, predicted deleterious, within autozygome), and (b) the nature of the gene (implicated in autism pathogenesis PMID: 26446216) |
| 16W-0218 | GRSF1:NM_001098477:exon3:c.88C>T:p.R30X | Het | Speech delay, intellectual disability/MR, learning disability, developmental regression, seizures- tonic–clonic, refractory epilepsy, neuro regression | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (implicated in brain development PMID: 18593884)//Novel candidate |
| 16W-0115 | GRTP1:NM_001286732:exon6:c.698G>A:p.W233X | Hom | Unexplained cholestasis with elevated liver enzymes | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (encodes a liver-enriched protein PMID: 11564724) |
| 16W-0277 | HID1:NM_030630:exon19:c.2318dupC:p.P773 fs | Hom | Failure to thrive, growth retardation/short stature, intellectual disability/MR, agenesis for corpus callosum, hypotonia, panhypopituitarism, similar F/H form sever maternal cousins (males) likely X- linked one bother dies at age of 6 months, 2 sons of his aunt dies with similar problem but no diagnosis, hypoglycemia, central hypothyroidism, central adrenal insufficiency, post meningitis | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (required for homotypic fusion of immature secretory granules during maturation PMID: 27751232) |
| 16-2731 | IFNL1:NM_172140:exon3:c.305T>C:p.L102P | Failure to thrive, microcephaly, fine motor delay, gross motor delay, speech delay, agenesis of corpus callosum, migration disorder, hypotonia, scoliosis, absent thumb, IUGR, external ear malformation, epilepsy and skeletal abnormalities | (a) The nature of the variant (predicted deleterious, novel, within ROH) and (b) the nature of the gene (involved in DNA damage repair, a mechanism that is impaired in several syndromes with overlapping clinical features (PMID: 25692705) | |
| 16W-0222 | KCNC4:NM_001039574:exon1:c.23C>T:p.S8F | Het | Ataxia, dystonia | (a) The nature of the variant (novel, predicted deleterious), (b) its known expression pattern in brain and altered expression in patients with neurodegenerative diseases (PMID: 21912965) |
| 16W-0292 | LRRC52:NM_001005214:exon2:c.659delT:p.L220 fs | Het | Muscle weakness | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (modifies BK potassium channels and is strongly expressed in skeletal muscles PMID: 22547800) |
| 16W-0157 | MAP7D3:NM_001173517:exon7:c.804_805insTA:p.D269_A270delinsX | Hemi | ADHD with GDD, no speech, mild hepatosplenomegaly | (a) The nature of the variant (novel and truncating) and (b) the nature of the gene (expressed in brain and suggested to play a role in ID PMID: 24817631) |
| 16W-0191 | MCTP2:NM_001159644:exon5:c.384dupT:p.N128 fs | Hom | AV pulmonary AV malformation, Failure to thrive, growth retardation, speech delay, learning disability, hearing loss, nephrotic syndrome | (a) The nature of the variant (novel and predicted deleterious) and (b) the nature of the gene (PLI score of 0.98 and the neurological phenotype in the mouse model PubMed: 22198669) |
| 16W-0176 | MED26:NM_004831:exon3:c.1771T>G:p.L591 V | Het | Fine motor delay, speech delay, intellectual disability/MR, stereotypic behaviours | (a) The nature of the variant (novel and predicted deleterious) and (b) the nature of the gene (PLI socre of 0.95 and established role in regulating neuronal gene expression PMID: 19049968) |
| 16W-0204 | MPP7:NM_173496:exon16:c.1251C>G:p.Y417X | Hom | Ataxia | (a) The nature of the variant (novel, predicted deleterious and within autozygome) and (b) the nature of the gene (encodes a member of membrane-associated guanylate kinase (MAGUK) family of proteins, which are implicated in synapse formation and function PMID: 21739617) |
| 16W-0288 | MRPS35:NM_021821:exon1:c.112+1->T | Hom | Failure to thrive, fine motor delay, gross motor delay, speech delay, intellectual disability/MR, brain atrophy, abnormal shaper of skull and limbs, facial dimorphism. | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (the same family of proteins has been implicated in a number of mitochondrial multisystem disorders) |
| 16W-0219 | MTDH:NM_178812:exon6:c.862delG:p.E288 fs | Hom | Growth retardation/short stature, fine motor delay, gross motor delay, speech delay, intellectual disability/MR, learning disability, developmental regression, autism spectrum disorder, autistic features, stereotypic behaviours, other psychiatric symptoms | (a) The nature of the variant (homozygous truncation), (b) it is known to be expressed in brain and has been extensively studied in the context of glioma (PMID: 28107197) |
| 16W-0304 | MTMR9:NM_015458:exon9:c.1415A>T:p.N472I | Hom | Gross motor delay, speech delay, intellectual disability/MR, seizures, two sisters are similarly affected | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (MTMR7 forms a complex with MTMR9 and dephosphorylates phosphatidylinositol 3-phosphate and Ins(1, 3)P2 in neuronal cells PMID: 12890864 |
| 16N-0329 | NECAP2:NM_001145277:exon3:c.212C>A:p.A71D | Hom | GDD and cataract | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (mutations in its paralog NECAP1 cause GDD PMID 24399846) |
| 16-2728 | NPAT:NM_002519:exon17:c.3644C>T:p.S1215L | Het | Psychomotor retardation, seizures disorder, Angelman syndrome | (a) The nature of the variant (predicted deleterious, novel) and (b) the nature of the gene (low %HI score in DECIPHER and involved in chromatin remodelling which is a common mechanism in neurodevelopmental disorders |
| 16W-0086 | NRAP:NM_001261463:exon5:c.400_407del:p.C134 fs | Hom | Cardiomyopathy (dilated) | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (implicated in cardiomyopathy pathogenesis in mouse PMID: 21276443) |
| 16W-0210 | PAX7:NM_001135254:exon3:c.433C>T:p.R145X | Het | Hypotonia, exercise intolerance/easy fatigue, muscle weakness, stroke/stroke-like episodes, recurrent headache/migraine, creatine phosphokinase abnormalities | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (low %HI of 11.2, established role in skeletal muscle development PMID: 21954137) |
| 16W-0150 | PCNX:NM_001308160:exon26:c.4804A>G:p.K1602E | Het | Atrial septal defect, ventricular septal defect, failure to thrive, fine/gross motor retardation, brain atrophy, dandy walker variant, hypotonia, hypertonia, seizures myoclonic, spasticity, prematurity, IUGR, gastrointestinal reflux, 8 months old female with GDD-epilepsy, SHC, abnormal karyotype 46 XX add 3P | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (high PLI of 1 and established expression in mouse brain) |
| 16W-0148 | PLCH2:NM_001303012:exon16:c.2132G>A:p.C711Y | Hom | Failure to thrive, fine motor delay, gross motor delay, speech delay, autistic features, hypotonia, seizure, white matter changes in bilateral p…, poor vision, GDD and epilepsy | (a) The nature of the variant (novel, predicted deleterious and within ROH) and (b) the nature of the gene [its ortholog PLCH1 mutations causes an overlapping phenotype (PMID: 28413018)] |
| 16W-0083 | PLEKHF1:NM_024310:exon2:c.514C>T:p.R172C | Hom | Myopathy, cardiomyopathy (Dilated), muscle weakness | a) The nature of the variant (novel, predicted deleterious, within autozygome) and b) the nature of the gene (highest expression was detected in heart and skeletal muscle) |
| 16N-0289 | PTPN12:NM_001131009:exon12:c.904C>T:p.R302X | Het | Multiple epiphyseal dysplasia | (a) The nature of the variant (novel, truncating) and (b) the nature of the gene (it has a PLI score of 1, and is involved in the regulation of multimeric protein complexes in podosomes of osteoclasts PMID 16052478) |
| 16W-0097 | QKI:NM_206853:exon6:c.635-2A>T | Het | Dystonia, (the rest is unclear) | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (high PLI score of 0.96 and established mouse model that manifests severe neurological disease PubMed: 8589716) |
| 16N-0249 | RILPL2:NM_145058:exon1:c.161C>T:p.A54 V | Hom | Skeletal dysplasia, very mild speech delay, gross motor delay, learning disability, facial dysmorphism | (a) The nature of the variant (novel, predicted to be deleterious and within a run of homozygous) and (b) the nature of the gene (this is a candidate ciliopathy gene as per PMID: 23264467 so this may represent a skeletal ciliopathy |
| 16W-0154 | RIMKLA:NM_173642:exon1:c.18G>A:p.W6X | Hom | Recurrent chest infection, sickle cell trait, recurrent spells of absent spells, carrier of MEVF gene, IEG negative | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (enzyme responsible for making NAAG, an endogenous peptide abundant in mammalian nervous systems PMID: 16127367) |
| 16-2732 | RIMS2:NM_014677:exon2:c.418C>T:p.R140C | Het | Lower limb muscle weakness and spasticity, periventricular leukomalacia, normal CK | (a) The nature of the variant (novel and predicted deleterious) and (b) the nature of the gene (PLI of 1.00 and established role in synapse formation PubMed: 12620390) |
| 16W-0075 | RNF213:NM_001256071:exon60:c.14394delC:p.F4798 fs | Het | Autism spectrum disorder | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (associated with CNS vascular malformation PMID 27745834) |
| 16W-0152 | ROBO1:NM_133631:exon21:c.2990A>T:p.D997 V | Het | Intellectual disability, epilepsy, autism, ADHD, mitral regurgitation | (a) The nature of the variant (novel and predicted deleterious) and (b) the nature of the gene (%HI of 3, and suggested link to autism PMID: 18270976) |
| 16-2670 | SEC16A:NM_001276418:exon5:c.3820C>T:p.R1274C | Hom | Microcephaly, fine motor delay, gross motor delay, speech delay, abnormal nails—small fingers, flat feet, short stature | (a) The nature of the variant (predicted deleterious, novel, within autozygome) and (b) the nature of the gene (involved in proliferation PMID PMID: 25526736) |
| 16N-0301 | SIAH1:NM_001006610:exon1:c.91_91del:p.E31 fs | Hom | Developmental delay, seizure disorder | (a) The nature of the variant (novel, truncating) and (b) the nature of the gene (it functions as an E3 ubiquitin ligase that binds to two presynaptic active zone proteins Piccolo and Bassoon PMID: 28231469) |
| 16-2718 | SIRT2:NM_001193286:exon3:c.70G>T:p.E24X | Hom | Microcephaly, fine/gross motor delay, speech delay, learning disability, developmental regression, periventricular leukomalacia, prematurity, oligohydramnios, nystagmus, recurrent fever | (a) The nature of the variant (predicted deleterious, novel, within autozygome) and (b) the nature of the gene (implicated in myelination PMID:21949390) |
| 16W-0147 | SLAIN2:NM_020846:exon5:c.938C>T:p.T313I | Het | Microcephaly, learning disability, developmental regression, sever hypotonia, seizures (?infantile spasms), delayed myelination, sever epileptic encephalopathy (1.5) | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (high PLI of 0.88 and established role in neuronal development PMID: 23077057) |
| 16W-0319 | SLC22A20:NM_001004326:exon4:c.763+1G>A | Hom | Epilepsy, GDD, fine motor delay, gross motor delay, speech delay, intellectual disability learning disability, stereotypic behaviors, dystonia, hypotonia, seizures (GTC), spasticity | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (high expression in rat olfactory bulb and forebrain PubMed: 17714910) |
| 16W-0283 | SMDT1:NM_033318:exon2:c.255C>G:p.S85R | Hom | LGMD?, dystonia | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (encodes EMRE, an essential component of mitochondrial Ca uniporter, which has been implicated in mitochondrial myopathies PMID: 24231807) |
| 16W-0193 | SRRT:NM_001128852:exon5:c.497C>T:p.T166 M | Het | Failure to thrive, fine motor delay, gross motor delay, speech delay, intellectual disability | (a) The nature of the variant (novel and predicted deleterious) and (b) the nature of the gene (PLI score of 0.98 and the neurological phenotype in the mouse model PubMed: 22198669) |
| 16-2541 | SSTR1:NM_001049:exon3:c.1169_1170insGCTCTGAGCCCGGGCCACGCAGGG:p.T390delinsTLX | Hom | Hypotonia, developmental delay | (a) The nature of the variant (novel, within autozygome and predicted deleterious), and (b) the nature of the gene (this serotonin receptor is strongly expressed in brain and GI tissues, has been linked to neuroendocrine tumors that manifest as unexplained diarrhea and the knockout mouse has hypoactivity (PMID 7777168) |
| 16W-0263 | ST20:NM_001100879:exon3:c.135T>A:p.C45X | Het | No information | (a) Nature of the variant (novel and truncating), (b) the gene is known to be a tumor suppressor so it is conceivable that this patient’s germline ST20 variant may have predisposed her to the bilateral optic nerve tumor observed. Confirming LOH in a tumor sample will greatly corroborate this hypothesis and this can be done on research basis (please contact lab director to coordinate) |
| 16-2752 | SYT9:NM_175733:exon7:c.1471C>T:p.R491X | Hom | Seizures, retinitis pigmentosa, obesity | (a) The nature of the variant (predicted deleterious, novel) and (b) the nature of the gene (%HI score of 14, and its deficiency in mouse causes severely impaired synaptic transmission (PubMed: 17521570) |
| 16W-0255 | TSPAN6: NM_001278740:exon7:c.513+4C>T | Hemi | Fine motor delay, gross motor delay, speech delay, intellectual disability, learning disability, head nodding nystagmus, increase myopia, decrease vision with age, previous neuro-panel negative | (a) The nature of the variant (novel, predicted deleterious, hemizygous) and (b) the nature of the gene (regulates hippocampal synaptic transmission and long term plasticity PMID: 28207852) |
| 16-2737 | UBR4:NM_020765:exon22:c.2873C>A:p.S958Y | Het | Developmental regression, brain atrophy, ataxia, | (a) The nature of the variant (predicted deleterious, novel) and (b) the nature of the gene (PLI score of 1.00, involved in ubiquitin ligation, a mechanism that is impaired in several neurodegenerative diseases, the presence of another case with early dementia and mutation in the same gene) |
| 16-2768 | UBR4:NM_020765:exon66:c.9787G>A:p.A3263T | Het | Behavioral changes starts 4 year ago, then seizures, finally developed dementia white matter changes. | (a) The nature of the variant (predicted deleterious, novel) and (b) the nature of the gene (PLI score of 1.00, involved in ubiquitin ligation, a mechanism that is impaired in several neurodegenerative diseases, the presence of another case with early dementia and mutation in the same gene) |
| 16W-0282 | VAMP4:NM_001185127:exon5:c.175G>A:p.V59 M | Hom | Microcephaly, speech delay, intellectual disability/MR, cataracts | (a) The nature of the variant (novel and predicted deleterious), and (b) the published role of VAMP4 in synaptic transmission (PMID: 22406549) |
| 16W-0233 | VPS36:NM_001282169:exon14:c.894-2->T | Hom | Speech delay, intellectual disability/MR | (a) The nature of the variant (novel, predicted deleterious, within autozygome) and (b) the nature of the gene (mutations in other components of ESCRT-II are also known to cause ID such as PMID: 22717650) |
| 16W-0197 | WDR59:NM_030581:exon4:c.270G>A:p.W90X | Het | Fine motor delay, gross motor delay, dystonia, hypertonia, seizures: Inf. spasm, spasticity | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (encodes a component of GATOR complex, which is implicated in familial focal epilepsies and focal cortical dysplasia PMID 27173016) |
| 16N-0291 (duo) | WDYHV1:NM_001283024:exon5:c.256C>T:p.R86X | Het | Father of an affected child | (a) The nature of the variant (extremely rare, truncating) and (b) the nature of the gene (it encodes NTAQ1, a component of the N-terminal pathway in mammalian cells, which has been implicated in the pathogenesis of neurodegenerative diseases PMID: 23499006) |
| 16W-0295 | WHSC1:NM_001042424:exon13:c.2518+1G>A | Het | Failure to thrive, facial dysmorphism, triangular face mild | (a) The nature of the variant (novel, predicted deleterious) and (b) the nature of the gene (pLI 1.00, this gene has long been suspected to be the candidate gene for Wolf-Hirschhorn syndrome, which has significant overlap with the provided features PubMed: 19483677) |