Table 1.

ALMS1 mutations, protein expression of ALMS1 in dermal fibroblasts, and clinical phenotypes of patients studied. All sequence variants are numbered according to canonical ALMS1 transcript ENST00000613296.4. Underlined mutations are predicted to truncate the ALMS1 protein before the epitope recognized by the anti‐ALMS1 antibody used for immunofluorescence. Missense mutations are shown in bold. Allele frequency of those mutations in the ExAC database is indicated in brackets after these

Patient	ALMS1 genotype	ALMS1 detection	Ciliogenesis	Vision	Hearing	Heart	Obesity?	Metabolism	Liver	Kidneys	Other
P1	p.Arg578Glyfs*17/p.Gln3494*	− PF ± M	Normal	NP 6 m RB 10y	BHA (15y)	Severe fibrosis IHD (35y)	Yes (childhood)	AN DM (14 y) Severe MDL	Fibrosis (25y)	CKD3 (30y)	Died pneumonia (39y)
P2	p.Asn2945Lys (1.0%)/p.Lys2196Serfs*10	± PF + M	Normal	NP 3 m VA 6/36 (24y)	BHA (10y)	Mild fibrosis	No (BMI 26, WHR 0.84 (23y))	AN (8y) DM (10y)b Mild MDL	Fibrosis (23y)	Normal (23y)
P3	p.Thr3591Lysfs*6/p.Arg3805*	− PF − M	Normal	NP 3 m RB 4y	BHA (10y)	PTCA (37y)	Yes (BMI 34, WHR 1.05 (38y))	AN (5y) DM (15y) Severe MDL	Fibrosis (34y)	CKD5 (38y)	Died pneumonia (43y)
P4	p.Arg2669*/p.Arg3628*	− PF − M	Normal	NP 6 m RB 10y	BHA (9y)	Severe fibrosis	No (BMI 28, WHR 0.92 (27y))	AN (6y) DM (14y) Mild MDL	Fibrosis (20y)	Normal	Kyphoscoliosis
P5	pGln3494*/p.Thr3591Lysfs*6	− PF − M	Normal	NP 48 m RB 15y	14y	Mild fibrosis	Yes (16y) (WHR 1.0 (45y))	AN DM (36y)	Fibrosis	CKD3 (42y)	Forestier's disease
P6	p.His3881Tyr (0.1%)/p.Val423Ile (0.3%)	± PF + M	Normal	NP 144 m RB 30y	Mild deafness No HA	Fibrosis (37y)	Yes (BMI 35, WHR 1.0 (33y))	AN DM (teens) MDL Severe IR	Fibrosis (36y)	RT (c.20y)
P7	p.Ser3960Phefs*12/WT	± PF + M	Normal	NP 120 m RB 37y	Sensorineural deafness (18y) BHA 30y	Fibrosis (50y)	Yes (BMI 32.2, WHR 1.0 (25y))	AN severe IR Mild MDL	NAFLD Fibrosis	CKD3	2 brothers with cardiomyopathy, blindness, deafness
P8	p.Gln3000*/WT	− PF − M	Normal	NP 18 m RB 6y	7y	Normal	Yes (BMI 42, WHR 0.87 (40y))	Severe IR DM (35y)	NAFLD Fibrosis	CKD3 (42y)
P9	p.Gln3816*/p.Val2300Trpfs*43	− PF − M	Normal	NP 12 m RB 5y	12y	Normal	Yes (BMI 34.4, WHR 1.0 (31y))	AN DM (18y)	NAFLD	No	Mild kyphoscoliosis.
P10	p.His624Arg (1.9%)/WT	+ PF + M	Normal	NP 360 m perceives light (43y)	Mild deafness (42y)	No	Yes	DM (30y)	Normal	No	Sibling died in infancy, heart failure.
P11	p.Thr3591Lysfs*6/p.Asn1787Asp (1.4%)	− PF − M	Normal	NP <2 m RB 10y	BHA	No	Yes	MDL IGT	NAFLD	No	Hypothyroid
P12	p.Ser1382*/p.Gln3000*	− PF − M	Normal	NP <3 m RB 10y	BHA	No	Yes	MDL IGT	NAFLD	No
P13	p.Thr3591Ilefs*5/p.Thr3591Ilefs*5	− PF − M	Normal	NP <3 m RB 10y	BHA	Yes	Yes	No	No	No
P14a	p.Ser1645*/p.Ser1645*	− PF − M	Normal	NP 1 m	BHA	No	Yes	No	NAFLD	No
P15a	p.Ser1645*/p.Ser1645*	− PF − M	Normal	NP <3 m RB 13y	BHA	No	Yes	DM Severe MDL	Yes	No
P16	p.Gln2979*/p.Asn1787Asp (1.4%)	− PF ± M	Normal	NP <3 m RB 12y	BHA	No	Yes	No	No	No
P17	p.Leu940*/p.Thr2457Thrfs*18	− PF − M	Normal	NP <3 m	BHA	No	Yes	Yes	No	No	Kyphoscoliosis
P18	p.Thr3591 fs*6/p.Ser1948 fs	− PF − M	Normal	NP <3 m RB 7y	BHA	No	Yes	No	No	No
P19	p.Thr3591 fs*6/p.Ser1948 fs	− PF − M	Normal	NP <3 m	BHA	Yes	Yes	No	No	No
P20	p.Thr3591Lys fs*6/p.Gln3494*	− PF − M	Normal	NP <3 m	BHA	Yes	Yes	No	No	No
P21	p.Trp266*/p.Arg3702*	± PF + M	Normal	NP 18 m	No	Yes (3 m) HT	No	No	No	No	Hypertension
P22	p.Arg2927*/p.Arg2927*	− PF − M	Normal	NP <3 m RB 11y	BHA	No	Yes	Yes	No	No
P23	p.Ser1645*/p.Ser1645*	− PF − M	Normal	NP <3 m	No	Yes (CM)	Yes	No	No	No

PF, paraformaldehyde fixation; M, methanol fixation. “+” = normal intensity of ALMS1 immunostaining; “−” = absent staining; “±” = weak staining. NP = age at development of nystagmus and/or photophobia. RB = age when registered blind; (B)HA = (Bilateral) hearing aids. Cardiac fibrosis was detected by MRI. HT, heart transplantation; BMI, body mass index; WHR, waist:hip ratio; AN, acanthosis nigricans; MDL, metabolic dyslipidemia, denoting elevated plasma triglyceride and suppressed HDL cholesterol; DM, diabetes mellitus; IR, insulin resistance; IGT, impaired glucose tolerance; NAFLD, nonalcoholic fatty liver disease; CKD, chronic kidney disease; RT, renal transplantation; PCR studies of ALMS1 cDNA showed no evidence of exon skipping for P6, P7, P10, P11, nor P15. P6 and P7 underwent exome sequencing as described in text, and compound heterozygous pathogenic BBS2 mutations were later found in P6.

^aP14 and P15 are siblings.

^bP2 became absolutely insulin deficient with detectable anti‐glutamic acid decarboxylase antibodies at 20 years old.