Table 1

Phenotypes of COACH subjects with MKS3, RPGRIP1L and CC2D2A mutations

Pedigree	Mutations	Amino acid	Age/sex	CNS	Liver	Col	RD	Renal	Other
MKS3
UW51	c.1046T>C	p.L349S	21y/M	MTS (CT)	ELE(18 mo), PH(12y)	+	−	−	AB, ptosis
	c.2498T>C	p.I833T			Bx(1y,12y): BDA, prog CHF
					Tx(17y)
UW54	c.675G>A	p.W225X	11y/F	MTS	ELE(9y)	+L	−	−	AB, ptosis, small stature
	c.389C>G	p.P130R
UW56	c.515G>A	p.R172Q	17y/M	MTS	ELE(10y), PH(15y)	+R	−	−	−
	c.769A>G	p.M257V			Bx(12y): BDA, CHF
					ursodiol
UW57	c.2825T>G	p.F942C	2y/M	MTS	ELE(<2y)	+	−	−	AB
	c.978+3 A>G	Spl							Micropenis
UW60	c.1046T>C	p.L349S	3y/F	MTS	ELE(3y)	−	−	−	AB
	c.1843T>C	p.C615R
UW61	c.2522A>C	p.Q841P	5y/F	MTS	ELE(3y)	+	−	MKD	AB
	c. 622A>T	p.R208X			Bx(3y): CHF
UW62	c.1115C>A	p.T372K	10y/F	MTS	HSM(6 m)	−	−	NPH	AB
	c.1115C>A	p.T372K			Bx(6 m): BDA, DPM, CHF
	c.2322+3 Ins(T)*†	Spl
UW63	c.2498T>C	p.I833T	14y/F	MTS	Bx(14y): BDA, CHF	+	−	CRF, NPH, ESRD(13y)	AB, anterior anus
	c.1351C>T	p.R451X						Tx(14y)
UW64	c.300C>A	p.C100X	4y/F	MTS	HSM(2y)	+	−	−	AB
	c.2498T>C	p.I833T			Bx(2y): BDA,CHF
					ursodiol
UW65	c.1321C>T	p.R441C	9y/M	MTS	ELE, HSM(11 mo), SM(9y)	+	−	−	Hypogonadism
	c.1453C>T	p.P485S			Bx(11 mo, 9y): BDA, CHF (fig 1C,D)
UW05	c.1126C>G	p.Q376E	14y/F	MTS	ELE, abn US, PH(13y)	+	−	−	AB
	c.1674+3A>G‡	Spl			Bx(14y): CHF				Fetal sibling: MKD
					PSS(14y)
UW30-4	c. 1073T>C	p.P358L	Birth/F	−	Ax: HSM, BDA	NA	NA	MKD	Dysmorphic
	c. 1911A>C	p.F637L	dec
UW30-3	c. 1073T>C	p.P358L	1 m/M	MTS	NA (Ax not done)	+	−§	MKD	AB
	c. 1911A>C	p.F637L	dec
UW30-5	c. 1073T>C	p.P358L	18 w/M	CVH	Ax: immature portal fields without evident ductal plate malformation	NA	NA	MKD	Dysmorphic
	c. 1911A>C	p.F637L	fetus	EC
UW83	c.1438A>G	p.Y513C	8y/F	CVH	ELE(4y)	+L	−	−	AB, ptosis
	c.2497T>C	p.I833T							sib: 20 wk M fetus CVH
UW84	c.725A>G	p.N242T	21y/M	MTS	HSM(7y), PH, HSP(8y)	−	−	CRF(16y) Bx(16y): ?NPH	Ptosis
	c.725A>G	p.N242T			Bx(7y): CHF			Rx
					Rx
UW73	c.1538A>G	p.Y513C	4y/M	MTS	ELE, HSM(3y)	−	−	−	familial (paternal) balanced translocation
	c.1843T>C	p.C615R			Bx(4y): BDA, CHF
UW59	c.108G>T	p.E361X	4y/F	MTS	ELE(1y), Abn US(4y)	+	−	−	AB, ptosis, IM
	c.2661+5 G>A*	Spl			Bx(3y): CHF
UW58	c.297G>T*¶	p.K99N	9y/M	MTS	ELE(4y)	+	−	−	AB
	c.2322+3 Ins(T)*†	Spl			Bx(5y): CHF				Seizures, dystonia
UW52-3	c.2802delA	p.G934GfsX26	9y/M	MTS	ELE(18 mo)	+R	−	−	−
	?	?
UW52-4	c.2802delA	p.G934GfsX26	4y/M	MTS	ELE, HSM(3y)	+	−	MKD	AB, ASD/VSD
	?	?
UW72	c.755T>C	p.M252T	5y/M	MTS	ELE(4y), abn US(5y)	+	−	MKD, CRF	AB, small stature, hypothyroid
	?	?						HTN
CC2D2A
UW67	c.3145 C>T	p.R1049X	3y/M	MTS	ELE(2y)	−	−	EK	AB
	c.3347 C>T	p.T1116M			Bx(3y): CHF			HTN
UW49**	c.3289delG	p.V1097FfsX1	22y/F	CVH/ACCHC	HSM (5y)	+	−	EK, NPH	AB, ptosis
	c.4582C>T	p.R1528C			Bx(6, 8, 10y): prog CHF (fig 1E,F)			HTN
					Tx(11y)
RPGRIP1L
UW04-3††	c.2413C>T	p.R805X	17 y/M	MTS	Bx(5y): BDA, CHF (fig 1G,H)	−	−	EK	AB
	c.1975T>C	p.S659P						Bx(5y):NPH
								Tx(5y)
No mutations
UW66	Negative	Negative	7.5y/F	CVH/ACC (CT)	Bx(<1y): CHF	−	−	−	AB, abn ears, IM, clubfoot

abn, abnormal; AB, abnormal respiratory control; ACC, agenesis of the corpus callosum; AT, cerebellar ataxia; Ax, autopsy; BDA, bile ductule abnormality (proliferation/persistence/dilation) or bile duct dilation on imaging/MRI; Bx, biopsy; C, cirrhotic features including hepatocellular damage/necrosis and evidence of regeneration; CB, cerebellum; CD, choreoathetosis/dystonia; CG, cholangitis; CH, chronic hepatitis; CHF, congenital hepatic fibrosis; CNS, central nervous system; Col, chorioretinal coloboma (bilateral unless otherwise stated); CRF, chronic renal insufficiency; CT, computed tomography scan; CVH, cerebellar vermis hypoplasia; dec, deceased; DPM, ductal plate malformation (classic ring); EC, encephalocele; EK, echogenic kidneys on US; ELE, elevated liver enzymes; ESRD, end stage renal disease; HC, hydrocephalus; HCV, hepatitis C; HD, haemodialysis; HM, hepatomegaly; HR, hyperreflexia; HSM, hepatosplenomegaly; HSP, hypersplenism; IM, intestinal malrotation; LK, large kidneys; MCM, mega cisterna magna; MKD, macrocystic kidney disease; MTS, molar tooth sign on brain MRI; MRI, magnetic resonance imaging; NA, not available/not specified/not known; NC, nephrocalcinosis; NPH, nephronophthisis; PD, polydactyly; PH, portal hypertension (includes complications of PH such as gastrointestinal bleeding/varices); PSS, portosystemic shunt (includes splenorenal, transjugular intrahepatic portosystemic shunts); RD, retinal dystrophy; RMC, renal microcystic disease; Rx, medications; Spl, predicted splicing defect; SZ, seizures; SK, small kidneys; SM, splenomegaly; Tx, transplant; US, ultrasound; V, ventricle(s).
All UW subjects had developmental delay/mental retardation, hypotonia and/or ataxia, oculomotor apraxia.
Age refers to age at last contact in years (y), months (m) or weeks gestation (w).
Laterality of manifestations is stated as either; R, right; L, left; or bilateral unless otherwise stated.
Outcome details are italicised and appear in the lower portion of the cell.
↵* Not seen in >192 control chromosomes.
↵† splicing of exon 22 was not affected in a lymphoblastoid cell line from UW58.
↵‡ results in the use of a cryptic splice within intron 16 and a premature termination codon one amino acid after exon 16.
↵§ fundus flavus noted on retinal exam.
↵¶ predicted to be benign by Polyphen and SIFT (see text).
↵** previously published in Gorden et al (2008).
↵†† brother without liver disease is listed in table 2.