Ciliopathies Flashcards
What are the ciliopathies
Heterogeneous group of genetic disorders caused by functional disruption of cilia, or by abnormal cilia biogenesis
What are the cilium important for
Left-right asymmetry in mammals
Non-motile cilium
Axo-ciliary synapse
Olfactory neurons, inner ear (smelling, hearing loss)
Motile cilium
Move fluids around cells (mucus clearance)
Ex: respiratory and reproductive tracts
general features of motile ciliopathies
Infertility
Hydrocephalus
Chronic respiratory problems
general features of immotile/ primary ciliopathies
Retinal dystrophy
Ansomia
Hearing loss
Central obesity
Skeletal anomalies (polydactyly, rib cage)
Hypogonadism
Genital anomalies
Ataxia, epilepsy, mental disability, brain malformations
Facial anomalies
Renal anomalies
Hepatic disease
Example of motile ciliopathy
Primary ciliary dyskinesia
Clinical features of primary ciliary dyskinesia
neonatal respiratory distress and adults have bronchiectasis
Chronic sinusitis and nasal congestion
Chronic and recurrent ear infections
Infertility
Situs inversus totalis 40-50%
Heterotaxy 12% :Discordance of right and left pattern of ordinarily asymmetric structures; Can be lethal
Primary ciliary dyskinesia MOI and genes
MOI: AR
Most common genes: DNAH5, DNAH11, DNAI1, CCDC39
Examples of non-motile ciliopathies
Bardet-Biedl
Jourbert
Alstrom
Polycystic kidney disease
MOI and genes for Bardet-Biedl
MOI: AR
BBS1 (most common; 23%) others are BBS2-12; BBS10 second most pop (20%)
_% of BBS are due to unknown cause; suspect _
20%, digenic
Major features of Bardet-Biedl
Retinal dystrophy (almost all)
Central obesity
Postaxial polydactyly
Cognitive impairment
Hypogonadism and GU anomalies
Kidney disease
Minor features of Bardet-Biedl
Neurologic abnormalities: DD, epilepsy, neuropsychiatric
Olfactory dysfunction
Oral/ dental abnormalities
Cardiovascular abnormalities
GI abnormalities: Hirschsprung, IBD, Celiac, and liver disease
Endocrine/ metabolic: hypothyroidism, type 2 DM, PCOS
MOI and genes for Jourbert syndrome
MOI: AR for all except OFD1 is X-linked
most common: TREM67, CEP290
Genes that overlap between BBS and Joubert
CEP290, MKS1, NPHP1
Top 3 clinical features for Joubert syndrome
Molar tooth sign (MTS)
Hypotonia
Developmental delays
Other features of Joubert
Cognitive impairment
Retinal dystrophy
Renal disease
Ocular colobomas
Occipital encephalocele
Hepatic fibrosis
Polydactyly
Oral hamartomas
Endocrine abnormalities
Both intra- and interfamilial variation are seen
MOI and gene for Alstrom
MOI: AR
ALMS1
Unique features for Alstrom
Short stature
Bilateral hearing loss
Hypothyroidism
Cardiomyopathy
Chronic respiratory tract infection
Hypertriglyceridemia
Hepatic disease
Key feature distinguishing Alstrom and BBS
Cardiomyopathy
Genes associated with Polycystic kidney disease
ARPKD: PKHD1
ADPKD: PKD1, PKD2
MOI and Gene for McKusick-Kaufman syndrome
MOI: AR
GENE: MKKS
Features of McKusick-Kaufman
Postaxial polydactyly and genitourinary malformations
unique: hydrometrocolpos , absence of obesity, DD and renal disease
MOI and genes for Meckel syndrome
MOI:AR
gene: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237
Meckel syndrome features
unique:
Perinatally lethal
Orofacial clefting
Posterior fossa abnormalities
Postaxial polydactyly
Polycystic kidney disease
Genitourinary malformations
Hepatic fibrosis
Other syndromes associated with polydactyly
diamond - blackfan anemia
Fanconi anemia
Ellis-van creveld syndrome
VACTERL
Trisomy 13 and 21
