Supplementary information: Clinical description of patients and families with mutations in the UPF3B gene

Supplementary table 2. Clinical features in affected males from families MRX62, N37 and S98.

MRX62 family
Patient / III-4 / III-7 / III-11 / III-16 / III-31 / IV-11 / IV-14 / IV-25
Age at examination (years) / 56 / 54 / 48 / 40 / 42 / 22 / 32 / 7
Height (cm) / 163 (-1.9 SD) / 158.5 (-2.6 SD) / 168 (-1 SD) / 170.5 (-0.6 SD) / 165 (-1.6 SD) / 169.5 (-0.8 SD) / 178 (+ 0.66 SD) / 114.5 (+1 SD)
Weight (kg) / 62.5 (+2.2 SD) / 58 (+0.4 SD) / 58 (+0.4 SD) / 62.5 (+2.2 SD) / 70 (+3 SD) / ND / ND / 17 (-2.3 SD)
OFC (cm) / 58.3 (+1.1 SD) / 58 (+0.9 SD) / 58.5 (+1.3 SD) / 57.2 (+0.3 SD) / 57.5 (+0.5 SD) / 59 (+1.7 SD) / 53.2 (+1.3 SD) / 53.9 (-2.2 SD)
Neurological examination / normal
stuttering / normal / muscle strength and tendon reflex diminished / normal
stuttering / increased tendon reflex / normal / normal / normal
Vision / - intermittent strabismus / - bilateral divergent strabismus / - divergent strabismus and bilateral cataract / - intermittent strabismus / - no strabismus / - intermittent divergent left eye strabismus / normal / normal
Seizures / no / no / no / no / yes, from age 23 / no / no / yes
Facial
dysmorphic features / - asymetric face
- widow’s peak
- no teeth
- large sticking-out ears / - short forehead
- widow’s peak
- most of the teeth absent
- dysmorphic sticking-out ears / - broad forehead
- asymetric face
- widow’s peak
- No teeth
- large sticking-out ears / - broad forehead
- midface hypotonia
- widow’s peak
- No upper teeth
- large ears / - high forehead
- asymetric face
- widows’ peak ? frontal boldness
- most of the teeth absent
- large ears / - high forehead
- asymetric face / no / no
Other malformative features / no / -unilateral macroorchidism / no / no / no / no / no / - radial unilateral hexadactyly
- hypospadias
- tracheo-esophageal
fistula
Figure / -slight knee and elbow valgus
- pronounced kyphosis, slight scoliosis
-large hands / - knee and elbow valgus
- pronounced kyphosis and scoliosis / - knee valgus
- kyphosis, slight scoliosis / - slight kyphosis / - elbow valgus
- pronounced kyphosis, slight scoliosis / - slight scoliosis / - spinal curve normal / - spinal curve normal
MR severity / moderate / severe / moderate / mild / Moderate / mild / mild / borderline
Behaviour / kind, friendly / jovial / shy, withdrawn / ND / ND / kind / ND / ND
N37 family / S98 family
Patient / II-1 / II-2 / S98
Age at examination (years) / 43 / 38 / 26
Height (cm) / 178 / 177 / 180
Weight (kg) / 83 / 82 / ??
OFC (cm) / 55.5 / 57 / 57
Neurological examination / ND / ND / stable tetraventricular hydrocephaly
Vision / ND / - myopia
- astigmatism
- nystagmus
- cataract (treated at 33 year-old) / - divergent strabismus
- bilateral cataract
Seizures / Yes, from 5 to 7 months of age / Yes, from 35 years of age / no
Facial
dysmorphic features / - Down slant of eyes
- brachycephaly / - mild midface hypoplasia / no
Other malformative features / no / no / double urethra at birth
Figure / ND / ND / - stiff gait with pronounced knee and foot valgus
- long thin hyper-extensible fingers and toes
MR severity / moderate-severe / moderate / borderline with autism
Behaviour / ND / ND / shy and withdrawn

. Height and OFC : standard deviation (SD) / age ; Weight : standard deviation (SD) / height

. ND: not documented

Clinical information:

Family MRX62:

Clinical examination was performed in eight affected males and five female carriers, and the findings were compared between patients and healthy male relatives in order to identify which traits were related to the condition. The clinical data are summarized in supplementary table 2 for the eight affected males. The disease was characterized in males, by variable degrees of mental retardation, normal physical measurements, spinal curvature abnormalities of variable severity (6/8 males), knee orelbow valgus(4/8 males) and strabism (5/8 males). A widows peak was observed in four affected males but also in the healthy twin brother of individual IV-11, large ears were reported in the four brothers in generation III but also in their healthy brother and father. None of the female carriers was mentally retarded and no abnormalities were observed on physical examination.

Family N37:

The index patient (II-1) was born after a normal pregnancy and delivery. His development was delayed. Unsupported walking was reached at the age of 2 years. He experienced seizures from 5 to 7 months of age. Thereafter no more seizures occurred. He was last examined at the age of 43 years. Findings are summarized in Table 2. Patient II-2 is a younger brother of II-1. He was born after an uneventful pregnancy with a birthweight of 9 pounds. His development was delayed. He reached unsupported walking at the age of 2 and half years and started to speak his first words at the age of 3 years. He was known to have vision problems, comprising myopia, astigmatism, nystagmus and cataract for which he was treated at the age of 33 years. At the age of 35 years epileptic seizures started. A cerebral CT scan at that age did not show abnormalities. EEG was abnormal suggesting a generalized type of epilepsy for which he started to use medication. He was last examined at the age of 38 years. Findings are summarized in Table 2. His total IQ measured 51.

Family S98:

The affected patient from family S98 is of Belgian origin and is the oldest child in a family of three, the younger brother and sister are healthy. Family history is negative regarding mental retardation or congenital anomalies. He was born after an uneventful pregnancy. At birth a double urethra was seen for which he was operated. His psychomotor development was reported to be slightly delayed, especially his motor milestones. He came to the hospital for the first time at the age of 6 years because of a recurrent headache. At that time a communicative hydrocephaly was seen on CT-scan, necessitating ventriculo-peritoneal drainage because of papilloedema. Hereafter, the hydrocephaly remained stable and he was headache-free. Because of learning problems and attention deficit disorder, he was placed in vocational education at the age of 12 years. During puberty his slender and marfanoid build became more obvious together with hyperlaxity and knee valgus, and a connective tissue disorder was suspected. However, no connective tissue abnormalities were detected in skin fibroblasts. Stapling was performed for the extreme bilateral knee valgus.

Because of difficult behaviour at primary and secondary school with outbursts of anger and impaired social interaction, he was seen several times by different child psychiatrists, who independently diagnosed him as borderline mental retardation with autism according to using ADOS .

At that time a genetic work-up was performed and showed a normal karyotype, absence of FMR1 expansion and exclusion of myotonic dystrophy. MRI of the brain showed a stable tetraventricular hydrocephaly, but no other anomalies. Now at the age of 26 years, he works in a sheltered environment. His height is 180 cm (72th percentile), arm span 189 cm and head circumference 57 cm (90th centile). He is not dysmorphic and has a rather stiff gait with pronounced knee and foot valgus. He has long thin hyperextensible fingers and toes. His behaviour is friendly but very shy and socially withdrawn. His mother who carries the same mutation has a normal phenotype.