Table 1 Summary of genetic and clinical findings in six families with likely causative variants in genes involved in GPI-anchor biogenesis

Decipher ID

257982

259633

258094

270250

263039

277013

Ethnicity and gender (parental relatedness)

Caucasian female (none)

White British Caucasian female (none)

Caucasian female (none)

Afghanistani male (first cousins)

Caucasian male (none)

Caucasian female (none)

cDNA; protein annotation (transcript ID)

c.[914A>G];[320C>T]

p.(D305G);(S107L)

(NM_033419.4)

c.[932T>G];[694 A>T]

p.(L311W);(K232*)

(NM_176787.4)

c.[1582G>A];[1730dupC]

p.(V528M);(L578fs*35)

(NM_015937.5)

c.[709G>C];[709G>C]

p.(E237Q);(E237Q)

(NM_015937.5)

c.[1306C>T];[713G>A]

p.(R436W);(G238D)

(NM_032634.3)

c.[48G>A];[336-2A>G]

p.(W16*);p.D113fs*2 due to skipping of exon 3, see Supplementary Figure S3.

(NM_004278.3)

Allele frequencies in ExAC V0.3^a

Not found in ExAC v0.3;

16/96 004

2/38 616;

Not found in ExAC v0.3

12/120 996;

3/118 342

8/100 744^b

1/120 802;

Not found in ExAC v0.3

1/121 332;

6/121 410

Year disease association published

2014⁹

2011²⁶

2013²⁷

2012³⁴

2012³⁷

Segregation in siblings (method)

Affected younger brother has both variants (Sanger sequencing).

Neither unaffected siblings are compound heterozygous (Sanger sequencing).

DNA from unaffected older sister not available.

Affected younger brother (270306) has both variants (Sanger and exome sequencing).

Unaffected older brother harbours neither variant (Sanger sequencing).

DNA from unaffected older brother not available.

Chances of seeing co-segregation under null hypothesis

1/4

(3/4)²

NA

1/4

3/4

NA

HPO terms

Bilateral ptosis, widely spaced teeth, wide mouth, pes planus, low-set ears, seizures, generalised neonatal hypotonia, cleft soft palate, Dandy–Walker malformation, moderate-to-severe cognitive impairment

Cognitive impairment, seizures, extrapyramidal dyskinesia

Oculomotor apraxia, absent speech, progressive cerebellar ataxia, ataxia, global developmental delay, motor delay, seizures, nephrolithiasis, cerebellar atrophy

270250: progressive microcephaly, EEG abnormality, seizures, intellectual disability profound, nystagmus, optic atrophy, poor suck

270306: seizures, progressive microcephaly, intellectual disability profound

Aganglionic megacolon, sensorineural hearing impairment, nail dysplasia, brachydactyly, aplastic/hypoplastic fingernail, global developmental delay, microcephaly

Moderate global developmental delay, renal cysts, cutis marmorata, broad hallux, pectus excavatum, wide mouth

Alkaline phosphatase result (normal range)

257982:

694 U/l (60–425).

Affected brother:

847 U/l (60–425).

199 U/l at 11.5 years, and 208 U/l at 12.5 years (normal range 130–390 U/l)

336 U/l at age 13 years (60–400 U/l).

Have been 119, 120, 119 and 170 U/l (normal range is 70–298 U/l)

270250:

Consistently low at 61–93 U/l (rising a little with age). Normal range is 135–530 U/l.

270306:

136 U/l. Normal range is 135–530 U/l.

Intermittently raised:

624 U/l and 418 U/l. Normal range is 60–425 U/l.

Persistently raised:

575 U/l at 1/52 of age

923 U/l at 3/12

819 U/l at 7 years

Normal range is 100–400 U/l.

Hand or foot abnormalities

257982:

Described to have ‘Tapering fingers’

Affected brother:

Described to have ‘small nails’

No abnormalities reported.

Tapering fingers

NA

Dystrophic 4th and 5th toenails; absent 5th fingernail.

Short fingers, clinodactyly and slightly broad halluces.

Microcephaly/OFC and other brain malformations

257982:

55 cm (+0.28 SDs) aged 12 years. MRI at age 2 ½ years detected a mild variant of Dandy–Walker malformation

Affected brother:

OFC of 51.5 cm aged 6 years (−1.2 SDs). MRI aged one year showed a mild generalised lack of white matter bulk and small olfactory bulbs.

At twelve months OFC on 50th centile

At age 6 years, HC on 75th centile. Brain scan indicated mild atrophy.

No microcephaly (53 cm 25–50th, centile aged 9 years).

Progressive isolated cerebellar atrophy affecting vermis and cerebellar hemispheres.

270250:

Microcephaly

270306:

Microcephaly

Reported to be microcephalic aged 2 ½ years.

No microcephaly – OFC 50–75th centile.

Brain MRI scan normal at 7 months of age.

Seizures

257982:

10 tonic seizures a day aged 2 years. Absence seizures and startle seizures which ceased aged 7/8 years.

Affected brother:

Absence seizures and startle seizures from the age of 2 years.

Developed epilepsy at age 2 years, which became very severe around age 5, but now (aged 14) is reasonably controlled.

3 febrile convulsions aged 1 year, long fits aged 2 years requiring PICU, generalised tonic–clonic seizures, EEG showed frequent runs of bilateral slow activity intermixed with sharp/spike waves.

270250: Neonatal onset epileptic encephalopathy, with multiple refractory seizures.

270306:

As above.

No seizures when last seen aged 2 years.

Brief generalised tonic–clonic seizures from 2 to 6 months of age but none since.