unaltered Supplement Ms 244-14-EJHGRR
Supplement: Clinical details of the patients listed in Table 1
Patients with a family history suggestive of XLID
Family 1: AP1S2 variant [NM_003916.3: c.367C>T; p.(Gln123*)]
In family 1, a family from Poland, the 25-year-old index patient had moderate to severe ID,
occasional aggressive outbursts and microcephaly [body measurements: height 180 cm (75th
centile), weight 65 kg (25-50th centile), OFC 52 cm (<3rd centile)]. Neither brain imaging nor
cerebrospinal fluid (CSF) tests were performed in this patient. He had had three affected male
maternal cousins. One of those cousins had hydrocephalus and died shortly after birth, and
another cousin died at age 3 years. The third cousin had moderate ID but was not seen by a
clinical geneticist.
The nonsense variant in AP1S2 was present in the index patient, his mother and in his
maternal grandmother. No other family members were available for testing.
Mutations in AP1S2 are associated with a syndromic form of XLID that is
characterized by elevated protein levels in CSF, calcifications of basal ganglia, hydrocephalus
and aggressive behavior (OMIM 300630). To date, only eight pathogenic AP1S2 variants
have been reported.1-5
Family 2: ATRX variant [NM_000489.3: c.6975+5G>A]
Psychomotor development of the 3-year-old index patient of family 2 was severely delayed
(walking at 25 months, no speech). He had microcephaly and borderline short stature. His 30year-old maternal uncle was said to be microcephalic in childhood, but OFC and height were
now at the 50th centile. The mother of the index patient and her second brother were healthy.
1
unaltered Supplement Ms 244-14-EJHGRR
The base pair exchange in ATRX intron 32 (c.6975+5G>A) was found in the index
patient, his mother and his affected uncle, but not in his healthy uncle. RT-PCR analysis of
DNA samples of the two patients revealed skipping of exon 32 (126 bp), which was predicted
to result in an in-frame deletion of 42 amino acids. X-inactivation in the mother was skewed
(95:5). HbH inclusion bodies in erythrocytes were detected neither in the index patient nor in
his affected uncle.
X-linked alpha-thalassemia/mental retardation syndrome (ATRX, OMIM 301040) is
characterized by ID and additional problems such as microcephaly and epilepsy.6 In some
patients, hemoglobin H (HbH) disease can be detected in a small percentage of erythrocytes,
but this was not the case in the present family. This family illustrates the role of intronic
variants, which are often difficult to interpret, as disease-causing factors.
Family 3: ATRX variant [NM_000489.3: c.6244G>A; p.(Asp2082Asn)]
In this family, two brothers aged 7 and 3 years, respectively, had severe ID, microcephaly and
short nasal septum. No tests for HbH inclusion bodies were performed in these brothers.
The missense variant in ATRX was present in both brothers and their mother.
Segregation of this variant with ID, evaluation as probably pathogenic by prediction programs
and the characteristic clinical features of the two patients support the causative role of this
variant.
Family 4: ATRX variant [NM_000489.3: c.7264_7265insT; p.(Gln2422Leufs*29)]
The index patient of this family had severe ID, secondary microcephaly, muscular hypotonia,
epilepsy, strabismus and short nasal septum. Remarkably, he had agenesis of the gallbladder.
He died at age 3 years 5 months of a respiratory infection. His younger brother had primary
microcephaly, micropenis, cryptorchidism and severely delayed psychomotor development.
He also had gallbladder agenesis.
2
unaltered Supplement Ms 244-14-EJHGRR
The ATRX frameshift variant was found in the index patient, his brother and in his
mother. Tests for HbH inclusion bodies were not performed.
Gallbladder agenesis has, to the best of our knowledge, only been described once in
association with ATRX syndrome [family 1 in Thienpont et al (2007)].7 The family reported
by Thienpont et al (2007) had an interstitial duplication harboring part of ATRX, but also an
additional, distally located duplication that included several genes. A causative role of this
second duplication for the gallbladder abnormalities could not be excluded. The family
reported here supports the assumption that ATRX variants are associated with gallbladder
agenesis, which might be an underdiagnosed feature.
Family 5: CUL4B variant [NM_003588.3: c.2469C>G; p.(Ile823Met)]
The 17-year-old index patient of this family had moderate ID, macrocephaly (OFC 60 cm,
>97th centile), short stature (height 163 cm, <3rd centile) and cryptorchidism. A submucous
cleft palate was surgically corrected, and ophthalmic examinations revealed bilateral partial
optic atrophy without deleterious effects on vision. A maternal uncle had similar clinical
problems, but neither cleft palate nor optic atrophy.
The missense variant in CUL4B was present in the index patient, his mother, the
affected maternal uncle and the maternal grandmother. The variant was not found in the
healthy brother of the mother. X-inactivation in the mother was skewed (91:9).
Mutations in CUL4B are associated with a syndromic form of XLID characterized by
macrocephaly, short stature, hypogonadism and additional problems (Cabezas syndrome,
OMIM 300354).8 The clinical problems of the two patients described here are in accordance
with previously reported patients with pathogenic CUL4B variants. Cleft palate and optic
atrophy have so far not been reported in association with CUL4B variants, and they might be
either rare manifestations of this defect or coincidental findings.
3
unaltered Supplement Ms 244-14-EJHGRR
Family 6: CUL4B variant [NM_003588.3: c.2060G>A; p.(Trp687*)]
The 30-year-old index patient of this family and his older brother had moderate ID,
macrocephaly and obesity. The CUL4B nonsense variant was found in both brothers and their
mother who was healthy. For a discussion of CUL4B-associated XLID, see family 5.
Family 7: IQSEC2 variant [NM_001111125.2: c.2662dup; p.(Ile888Asnfs*16)]
The index patient of this family suffered from severe non-syndromic ID, i.e. he had no other
significant clinical problems. He had a maternal uncle who also had non-syndromic ID, which
gave rise to the suspicion of a common X-linked defect in this family.
The frameshift variant in IQSEC2 was detected in the index patient. However, this
variant was neither present in his mother nor in his maternal uncle in whom no other genetic
defect has so far been detected.
Mutations in IQSEC2 are associated with moderate to severe non-syndromic ID
(OMIM 309530).9 Recently, IQSEC2 variants were also reported in male patients who, in
addition to ID, suffered from epilepsy, microcephaly and stereotypic hand movements.10, 11
This family illustrates that in non-syndromic ID, patients that appear to be linked by a
common genetic cause may still turn out to have different disorders.
Family 8: KDM5C variant [NM_004187.3: c.2047del; p.(Ala683Profs*81)]
The 14-year-old index patient of this family had severe ID, OFC at the 90th centile, short
stature and strabismus, while his younger brother also had short stature but moderate ID, OFC
at the 10th centile and cryptorchidism. Neither of the two brothers had additional
malformations nor significant facial dysmorphic signs.
The KDM5C frameshift variant was detected in the index patient, his affected brother
and in their healthy mother who had skewed X-inactivation (98:2).
4
unaltered Supplement Ms 244-14-EJHGRR
Mutations in KDM5C (formerly known as JARID1C and SMCX) are associated with
mild to severe ID and additional problems such as short stature, epilepsy, hyperreflexia, ataxia
and microcephaly (OMIM 300534).12-15
Family 9: KDM5C variant [NM_001146702.1: c.3084C>A; p.(Cys1028*)]
The 48-year-old index patient of this family had moderate ID. Apart from seizures which
started at the age of 6 years, he had no other major medical problems. His sister had mild ID.
On examination at age 47 years, she had short stature (height 148 cm, <3 rd centile),
microcephaly (OFC 50.5 cm, <3rd centile), and she was obese (weight 87 kg, >97th centile).
She also had strabismus and hyperopia, but no history of seizures. The mother had had
learning problems and had died at the age of 66 years. The younger brother of the index
patient was healthy.
The KDM5C nonsense variant was found in the index patient and in his sister, but not
in the healthy brother. X-inactivation in the sister was skewed (95:5).
In this family, two female carriers of this variant (the sister and the mother of the
index patient) had cognitive deficits which were, however, less severe than in the index
patient. Although most reported female carriers of KDM5C mutations were described as
normal, affected females have been observed before.13, 15
Family 10: MED12 variant [NM_005120.2: c.2444G>A; p.(Arg815Gln)]
In this family, both the index patient and his brother had moderate ID, short stature and
microcephaly. Their mother had learning problems. Clinical details of this family will be
reported separately (Maiwald et al, in preparation).
The MED12 missense variant was present in the index patient, his affected brother and
their mother, but not in the healthy brother and also not in the healthy sister.
5
unaltered Supplement Ms 244-14-EJHGRR
Missense mutations in MED12 are associated with FG syndrome (Opitz-Kaveggia
syndrome, OMIM 305450), Lujan-Fryns syndrome (ID with marfanoid habitus, OMIM
309520) and Ohdo syndrome (OMIM 300895).16-18
Family 11: OPHN1 variant [NM_002547.2: c.1489C>T; p.(Arg497*)]
The index patient and his younger brother had mild to moderate ID, cryptorchidism,
strabismus and slightly ataxic gait. The younger brother had multiple cysts in the left kidney.
Both brothers had borderline obesity; height and OFC were in the normal range. Brain MRI
scans revealed cerebellar hypoplasia and slight atrophy of the frontal cortex in both brothers.
The OPHN1 nonsense variant was present in both brothers and their healthy mother.
Mutations in OPHN1 are associated with ID and cerebellar hypoplasia (OMIM 300486), and
the clinical features of the present family are in accordance with those of previously published
patients.19-23
Family 12: UPF3B variant [NM_080632.2: c.1101G>C; p.(Lys367Asn)]
The index patient of this family had moderate ID. Facial dysmorphic features included
hypertelorism and epicanthus. His mother had mild ID and psychiatric problems. A maternal
uncle had severe ID but was not seen by a clinical geneticist.
The UPF3B missense variant was detected in the index patient, his mother and his
affected maternal uncle. X-inactivation in the mother was not skewed.
Mutations in UPF3B cause XLID with variable associated features such as
macrocephaly and autism (OMIM 300676). Only eight UPF3B mutations have been reported
to date.24-27
6
unaltered Supplement Ms 244-14-EJHGRR
Family 13: ZDHHC9 variant [NM_016032.3: c.286C>T; p.(Arg96Trp)]
The 15-year-old index patient of this large Turkish family had moderate ID and normal body
measurements. He had surgery for left-sided ureteropelvic junction obstruction at the age of
10 years and developed postoperative keloid. Apart from mild cutaneous syndactyly of the 2nd
and 3rd toes, he neither had malformations nor significant dysmorphic signs. Each of his three
maternal aunts had a son with ID of similar severity. Apart from strabismus in one of those
cousins, they had no additional medical problems.
The ZDHHC9 missense variant was present in the index patient, his mother, his
maternal grandmother, two of his maternal aunts and their affected sons (the third aunt and
her affected son were not available for testing). X-inactivation in the mother was normal, i.e.
there was no skewing.
Defects in ZDHHC9 were reported in association with XLID and marfanoid habitus
(OMIM 300799), and only six mutations in this gene were reported to date.28-31 The patients
in the family reported here had no marfanoid features.
Sporadic patients
Patient 14: CUL4B variant [NM_003588.3: c.429_431dup; p.(Ser146dup)]
This 13-year-old Turkish patient had borderline short stature (height 142 cm, 3rd centile) and
borderline microcephaly (OFC 52 cm, 3rd-10th centile). Weight was normal (40 kg, 25th
centile), but his body proportions gave the impression of central obesity. Hearing loss was
diagnosed at age 12 years. He had a coarse face, small ears, broad nose with bulbous nasal tip,
epicanthus, thick lips, everted lower lip, brachydactyly, bilateral 2/3 toe syndactyly, and
sandal gap.
7
unaltered Supplement Ms 244-14-EJHGRR
The CUL4B in-frame insertion of one amino acid (serine) was diagnosed in the index
patient. No other family members were available for testing.
Apart from borderline microcephaly which has so far not been described in association
with CUL4B mutations, the clinical features of this patient are in accordance with previously
reported patients. Also syndactyly of the second and third toes has been reported before.32
Patient 15: DLG3 variant [NM_021120.3: c.649C>T; p.(Arg217*)]
This patient had mild to moderate ID and seizures that started at age 3 years. He neither had
malformations nor facial dysmorphic signs, and brain MRI scan was normal. He had a healthy
sister and a healthy brother.
The DLG3 nonsense variant was present in the patient and his mother. X-inactivation
testing of the mother revealed a normal result, i.e. there was no skewing.
To date, only seven DLG3 mutations have been reported in XLID families whose
affected male members had moderate to severe but otherwise non-syndromic ID.33-36 None of
those patients had epilepsy, but seizures were reported in one obligate carrier female who also
had borderline IQ.34 Random X-inactivation in the mother of the present patient corroborates
the absence of skewing in carrier females of previously published families.
Patient 16: SLC9A6 variant [NG_017160.1: g.135067656_135067991del (GRCh37/hg19)]
This boy was conceived after anonymous egg donation. He was born in the 36th gestational
week with low birth measurements [length 46 cm (<3rd centile); weight 2410 g (<3rd centile),
OFC 32.5 cm (<3rd centile)]. Psychomotor development was severely retarded, and he had
seizures starting at age 2 years. On examination at age 4 years, he could neither walk nor talk,
and he had strabismus and an OFC of 46 cm (3 cm below the 3rd centile).
The complete exon 1 of SLC9A6 was found to be deleted in this patient. DNA samples
of his genetic mother (an anonymous Turkish egg donor) were not available.
8
unaltered Supplement Ms 244-14-EJHGRR
Mutations in SLC9A6 cause Christianson syndrome (OMIM 300243), which is
characterized by severe ID, seizures, ataxia and microcephaly.37-39 The clinical features of the
present patient corroborate the findings in previously published patients with SLC9A6
mutations. This case raises particular concerns in terms of recurrence risks because the
genetic mother was an egg donor.
Patient 17: SMC1A variant [NM_006306.2: c.1937T>C; p.(Phe646Ser)]
This patient was born to healthy and non-consanguineous Turkish parents in the 34th
gestational week by Cesarean section. He had low birth measurements [weight 1180g (<3 rd
centile), length 35 cm (<3rd centile), OFC 35 cm (<3rd centile)], congenital heart disease
(anomalous aortic arch, atrial septal defect, aberrant subclavian artery), cryptorchidism,
sensorineural hearing loss and bilateral inguinal hernias. On examination at age 5 years 8
months, he had short stature (101 cm, <3rd centile) and borderline microcephaly (49.5 cm, 3rd
centile). Facial dysmorphic features included triangular face, downslanting palpebral fissures,
strabismus, ptosis, small nose with anteverted nares, thin upper lip and dysplastic, low-set and
posteriorly rotated ears. He had single transverse palmar creases at his hands and thin legs,
but no hand or foot malformations. Psychomotor development was severely delayed; he was
unable to walk without support and could not talk.
The SMC1A missense variant was detected in the patient and his healthy mother. Xinactivation in the mother was skewed (96:4).
Mutations in SMC1A are associated with Cornelia de Lange syndrome 2 (CDLS2,
OMIM 300590), and mutations have been reported in both male and female patients.40-43 The
clinical features of the present patient are in accordance with Cornelia de Lange syndrome.
9
unaltered Supplement Ms 244-14-EJHGRR
Patient 18: UBE2A variant [NM_003336.2: c.387dup; p.(Tyr130Valfs*9)]
This patient was born at term with large body measurements (length, weight and OFC were
above the 97th centile). He had congenital heart disease and suffered from muscular hypotonia
and feeding difficulties. Seizures started in the first months of life. Psychomotor development
was severely retarded. Brain MRI scans revealed progressive brain atrophy. His parents and
siblings were healthy. Clinical details of this patient were reported separately [patient 6 in
Czeschik et al 2013).44
The UBE2A frameshift variant was detected in the patient but not in his mother, i.e. it
was a de novo variant.
UBE2A mutations are associated with Nascimento syndrome (OMIM 300860), a
syndromic form of ID characterized by large head circumference, facial dysmorphism,
onychodystrophy and hirsutism.44-46 The clinical features of this patient are in accordance
with those of previously published patients.
Female ID patient with skewed X-inactivation
Patient 19: IQSEC2 variant [NM_001111125.2: c.3163C>T; p.(Arg1055*)]
This 16-year-old female patient suffered from severe ID, epilepsy and borderline
macrocephaly. Her parents were healthy, and she had no other family members with ID or
epilepsy. XLID panel diagnostics was initiated because of strongly skewed X-inactivation
(97:3) and revealed the heterozygous nonsense variant in IQSEC2. The variant was not
present in her mother; the father was not available for testing.
For a discussion of IQSEC2 mutations in female ID patients, see the respective
paragraph in the “Discussion” in the main article.
10
unaltered Supplement Ms 244-14-EJHGRR
Patients in whom a specific syndrome was clinically suspected
Patient 20: SLC16A2 variant [NM_006517.4: c.590G>A; p.(Arg197His)]
This 17-year-old boy had severe ID and was neither able to walk nor to talk. He had spastic
paraplegia, dystonia, strabismus, optic atrophy, cryptorchidism, and short stature (150 cm,
<3rd centile). He was severely underweight (28 kg), and OFC was 54 cm (3rd-10th centile).
Brain MRI scan at age 2 years 6 months revealed severely delayed myelination. Testing of
thyroid parameters showed low T4, normal TSH, and elevated T3.
The clinical problems, and in particular the elevated T3, led to the clinical diagnosis of
Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523). AHDS is caused by mutations in
SLC16A2 which encodes monocarboxylate transporter 8 (MCT8), a thyroid hormone
transporter.
The SLC16A2 missense variant was detected in the index patient, his healthy mother
and his maternal grandmother. X-inactivation analysis in the mother revealed a normal result,
i.e. there was no skewing. The identical variant (published as NM_006517.3: c.G812A;
R271H) has been reported before in an unrelated AHDS patient.47 Functional analyses using
constructs with this mutation showed reduced T3 uptake into neuronal cells of only 20%
activity compared to wild-type MCT8.48
Patient 21: PHF6 variant [NM_032458.2: c.687T>A; p.(His229Gln)]
The 15-year-old index patient had moderate ID, short stature (152 cm, <3rd centile),
macrocephaly (59 cm, >97th centile), cryptorchidism, hypogenitalism, dental crowding,
11
unaltered Supplement Ms 244-14-EJHGRR
tapering fingers and facial dysmorphic signs (large ears, fleshy earlobes, synophrys, narrow
palpebral fissures). His older sister had learning problems and similar facial features.
The clinical features raised the suspicion of Börjeson-Forssman-Lehmann syndrome
(BFLS, OMIM 301900), a syndromic form of ID with obesity and characteristic facial
features.49-54 This clinical diagnosis was confirmed by the PHF6 variation in the index patient
that was also present in his sister and in his mother.
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