Table 1 Phenotype information for individuals with ERCC1 variants.

Family

1

1

2

3

4

4

5

ERCC1 variant 1, NM_001983.4 NP_001974.1

c.466 C > T p.Arg156Trp

c.466 C > T; p.Arg156Trp

c.466 C > T; p.Arg156Trp

c.466 C > T; p.Arg156Trp

c.466 C > T; p.Arg156Trp

c.466 C > T; p.Arg156Trp

c.790 G > C p.Ala266Pro

ERCC1 variant 2, NM_001983.4

NP_001974.1

c.321+61_525+132del

p?

c.321+61_525+132del

p?

c.466 C > T; p.Arg156Trp

c.703-2 A > G

p?

c.525+2 T > C

p?

c.525+2 T > C

p?

c.790 G > C

p.Ala266Pro

Sex

Female

Female

Male

Female

Male

Male

Female

Deceased?

no

no

no

yes

yes

No

no

Age at last assessment

18 y

15 y 10 m

3 y 11 m

11 y 9 m

8 y 4 m

11 y 7 m

16 y 10 m

Weight, centile

Height, centile

OFC, centile

28 kg ( < 1st, Z-8.8) 139 cm (Z-3.72)

NR

24 kg ( < 1s, Z-10)

135 cm ( < 1st, Z-4.2)

NR

8.745 kg ( < 1st)

77.5 cm ( < 1st)

46.2 (7^th)

20.8 kg ( < 1st)

129 cm ( < 1st)

49.5 cm

20.5 kg (2.7^th)

130.1 cm (53^rd)

45.7 cm at 35 months

-2.3 sd)

27.1 cm (2^nd)

142 cm (29^th)

48.5 cm (-3.5 sd)

42.5 kg (-2.5 SD)

158 cm (-1.5 SD)

53 cm (- 2 SD)

Dysmorphic features

Deep-set eyes

Micrognathia

Deep-set eyes

Retrognathia

Short palpebral fissures

Deep-set eyes

None reported

Triangular-shaped face, deep-set eyes

Petite facial features (small face and small, pointed nose)

Liver

Cholestatic liver dysfunction at 18 months. Progressed to liver failure and transplant aged 9 y

Liver impairment from 2 years, liver biopsy showed moderate number of double-nucleated hepatocytes, some with large nuclei and nucleoli

Progressed to liver failure and transplant aged 8 y

Neonatal cholestasis which resolved, then developed mild cholestatic hepatitis with normal synthetic function. Acute rise in AFP at 3 y 4 m with suspicious lesions identified on CEUS. Biopsies were consistent with HCC. The patient is undergoing transplant evaluation at time of manuscript preparation

Progressive cholestatic liver dysfunction at age 9 y

Metastatic multifocal HCC diagnosed leading to death aged 11 y 9 m

Cirrhotic liver with multiple nodules on presentation, biopsy showed HCC, macro-trabecular subtype. Acute on chronic liver failure with increasing liver transaminases/coagulopathy/encephalopathy after 1st cycle of chemotherapy. Died from multi-system organ failure aged 8 y 4 m

Surveillance due to brother’s HCC showed rising AFP and liver MRI showed suspicious lesions. Biopsies confirmed moderately differentiated multifocal HCC.

Received liver transplant at 10 y 11 m

Cryptogenic cirrhosis with bile duct proliferation, mild inflammation and degenerative changes, suggestive of chronic cholestatic disease. MRCP with multiple hypointense focal liver lesions, progressive in size and number (possibly dysplastic noduli) and stenosis in distal part of common hepatic duct

Kidney

Proximal tubular dysfunction with albuminuria and hypercalciuria. Kidney function fluctuated, with intermittent episodes of acute kidney injury, progressive kidney impairment, with increasing creatinine

levels and minimal response to acetyl cholinesterase

inhibition. Kidney ultrasound showed small echogenic kidneys with reduced corticomedullary differentiation. Progressed to stage 5 chronic kidney disease and is under consideration for a kidney transplant

Renal tubulopathy with mild kidney impairment,

with progressively increasing creatinine levels.

Ultrasound showed small kidneys with nephrocalcinosis.

Progressed to stage 5 chronic kidney disease and is under consideration for a kidney transplant.

Neonatal nephrocalcinosis, which resolved

Recurrent UTIs;

Kidney dysfunction (Glucosuria, proteinuria, hyperphosphaturia, metabolic acidosis, and hypophosphatemia - consistent with Fanconi renotubular phenotype)

Stage 3 AKI secondary most likely to cisplatin. Consistent with nephrotoxicity but greater than expected. Kidney biopsy: Severe tubular injury with reactive focal nuclear enlargement and mild glomerular injury with no definitive glomerulonephritis.

Mild impairment

Developed hypertension post-liver transplant

Normal kidney ultrasound,

BP and creatinine, but low free carnitine and glucosuria, suggestive of proximal tubular kidney dysfunction; further evaluation pending

Skin

Freckling on sun-exposed areas.

Six BCCs removed in teenage years

Freckling on sun-exposed areas.

Scalp BCC removed

Numerous café-au-lait macules.

Severe photosensitivity

Numerous freckles

Significant. photosensitivity

Malar freckling

Numerous café-au-lait macules

Severe photosensitivity

Freckling on sun-exposed areas

Photosensitivity

Café-au-lait macules

Ocular photosensitivity

yes

yes

yes

yes

Not reported

Not reported

yes

Development

Mild intellectual disability, IQ 68

Mild intellectual disability, IQ63

Mild developmental delay

Normal

Learning difficulties

ADHD

Intellectual disability

Normal

Brain MRI

Mild cerebral atrophy with moderate cerebellar atrophy and mild brainstem atrophy (age 12 y)

Normal MRI at 5 y. MRI age 10 y showed moderate cerebellar atrophy and mild cortical atrophy

Normal MRI at 15 m

NR

NR

NR

NR

Other

Pancreatic insufficiency

Type 1 Diabetes mellitus

Hypothyroidism

Ovarian failure

Ataxia, tremor

Moderate-severe restrictive lung disease

Kyphosis

Exocrine pancreatic insufficiency

Ovarian failure

Hypothyroidism

Ataxia, tremor

Myopia

Amblyopia

Steroid-induced diabetes

Motor tics, gait ataxia

Post-liver transplant developed Type 1 diabetes mellitus and esophageal candidiasis

Primary ovarian insufficiency

Missing permanent teeth

Thenar hypoplasia

Restricted range of movement in thumbs bilaterally

Recurrent lower airway infections and decreased FEV1 and FVC with negative reversibility test; further evaluation pending

Motor tics