Ciliopathies

Question 1

What are the ciliopathies

Answer 1

Heterogeneous group of genetic disorders caused by functional disruption of cilia, or by abnormal cilia biogenesis

Question 2

What are the cilium important for

Answer 2

Left-right asymmetry in mammals

Question 3

Non-motile cilium

Answer 3

Axo-ciliary synapse
Olfactory neurons, inner ear (smelling, hearing loss)

Question 4

Motile cilium

Answer 4

Move fluids around cells (mucus clearance)
Ex: respiratory and reproductive tracts

Question 5

general features of motile ciliopathies

Answer 5

Infertility
Hydrocephalus
Chronic respiratory problems

Question 6

general features of immotile/ primary ciliopathies

Answer 6

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

Question 7

Example of motile ciliopathy

Answer 7

Primary ciliary dyskinesia

Question 8

Clinical features of primary ciliary dyskinesia

Answer 8

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

Question 9

Primary ciliary dyskinesia MOI and genes

Answer 9

MOI: AR
Most common genes: DNAH5, DNAH11, DNAI1, CCDC39

Question 10

Examples of non-motile ciliopathies

Answer 10

Bardet-Biedl
Jourbert
Alstrom
Polycystic kidney disease

Question 11

MOI and genes for Bardet-Biedl

Answer 11

MOI: AR
BBS1 (most common; 23%) others are BBS2-12; BBS10 second most pop (20%)

Question 12

_% of BBS are due to unknown cause; suspect _

Answer 12

20%, digenic

Question 13

Major features of Bardet-Biedl

Answer 13

Retinal dystrophy (almost all)
Central obesity
Postaxial polydactyly
Cognitive impairment
Hypogonadism and GU anomalies
Kidney disease

Question 14

Minor features of Bardet-Biedl

Answer 14

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

Question 15

MOI and genes for Jourbert syndrome

Answer 15

MOI: AR for all except OFD1 is X-linked
most common: TREM67, CEP290

Question 16

Genes that overlap between BBS and Joubert

Answer 16

CEP290, MKS1, NPHP1

Question 17

Top 3 clinical features for Joubert syndrome

Answer 17

Molar tooth sign (MTS)
Hypotonia
Developmental delays

Question 18

Other features of Joubert

Answer 18

Cognitive impairment
Retinal dystrophy
Renal disease
Ocular colobomas
Occipital encephalocele
Hepatic fibrosis
Polydactyly
Oral hamartomas
Endocrine abnormalities
Both intra- and interfamilial variation are seen

Question 19

MOI and gene for Alstrom

Answer 19

MOI: AR
ALMS1

Question 20

Unique features for Alstrom

Answer 20

Short stature
Bilateral hearing loss
Hypothyroidism
Cardiomyopathy
Chronic respiratory tract infection
Hypertriglyceridemia
Hepatic disease

Question 21

Key feature distinguishing Alstrom and BBS

Answer 21

Cardiomyopathy

Question 22

Genes associated with Polycystic kidney disease

Answer 22

ARPKD: PKHD1
ADPKD: PKD1, PKD2

Question 23

MOI and Gene for McKusick-Kaufman syndrome

Answer 23

MOI: AR
GENE: MKKS

Question 24

Features of McKusick-Kaufman

Answer 24

Postaxial polydactyly and genitourinary malformations
unique: hydrometrocolpos , absence of obesity, DD and renal disease

Question 25

MOI and genes for Meckel syndrome

Answer 25

MOI:AR
gene: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237

Question 26

Meckel syndrome features

Answer 26

unique:
Perinatally lethal
Orofacial clefting
Posterior fossa abnormalities
Postaxial polydactyly
Polycystic kidney disease
Genitourinary malformations
Hepatic fibrosis

Question 27

Other syndromes associated with polydactyly

Answer 27

diamond - blackfan anemia
Fanconi anemia
Ellis-van creveld syndrome
VACTERL
Trisomy 13 and 21