Mutations in SETD2 Cause a Novel Overgrowth Condition
Mutations in SETD2 Cause a Novel Overgrowth Condition
Two heterozygous mutations in the SETD2 gene were identified in two patients with 'Sotos-like' syndrome. In proband 1, we identified a heterozygous c.820C>T (p.Gln274*) nonsense variant in the SETD2 gene ((Su(var)3–9, enhancer of zeste (E(z)) and trithorax (trx)) domain-containing protein 2) (MIM 612778) (RefSeq NM_014159.6). We also identified a heterozygous missense variant c.5444T>G (p.Leu1815Trp) in SETD2 in proband 2. None of the two variants were reported in dbSNP, the 1000 Genomes Project or in the Exome Variant Server. We confirmed the two mutations using Sanger sequencing. Proband 1 carrying a nonsense SETD2 mutation (c.820C>T; p.Gln274*) was adopted and her biological parents could not be tested. We confirmed that the SETD2 variant c.5444T>G (p.Leu1815Trp) found in proband 2 was not found in either of his parents, indicating that it was a de novo mutation (figure 1).
(Enlarge Image)
Figure 1.
Pedigree of the two patients with SETD2 mutations, supporting clinical features and confirmation by Sanger sequencing. Photos are published with the proxy consent of the parents and assent of the probands. Note the long face, slightly down-slanting palpebral fissures and pointed chin. The c.820C>T mutation (arrow) in proband 1 (adopted girl) and the de novo c.5444T>G mutation in proband 2 (arrow) were confirmed by Sanger sequencing.
Proband 1 was adopted when she was 4 months old. Her birth weight was 2850 g (25–50th centile), length was 50 cm (50th centile) and occipitofrontal circumference (OFC) was 34.5 cm (25–50th centile). Her development was considered as normal between 4 months and 3 years of age. She walked at the age of 14 months. Speech was slightly delayed. She was first seen at the genetic clinic at 7 years and 8 months of age for speech delay, overgrowth and overweight. Her weight was 75 kg (>97th centile), BMI was 23, height was 137 cm (>97th centile) and OFC was 57 cm (>97th centile). The clinical examination showed prominent forehead with high frontal hairline, downward slanting palpebral fissures, prominent mandible, long and large hands and feet. She had frequent ear and renal infections without any associated malformations. Ophthalmological evaluation, EEG, metabolic screen in blood and urine, endocrinologic screen were all normal. At 7 years and 8 months, CT scan showed mild ventricular dilatation. Her full-scale IQ score was 91, with a verbal IQ of 99 and a performance IQ of 80. Chromosome analysis showed a 46, XX karyotype, and CGH array gave a normal result. At a follow-up evaluation at 12 years and 2 months, weight was 84 kg (>97th centile), height 164 cm (>97th centile) and OFC was 60 cm. At 12 years and 2 months, MRI of the brain disclosed nodular and punctiform hypersignals at the anterior parts of corona radiate and in the centrum semi-ovale. Radiographs of lumbar and sacral vertebral column and pelvis were normal. Hand films revealed major advance in carpal and phalangeal bone age with a bone age of 10 years and 11 months then 16 years and 4 months at chronological ages of 7 years and 8 months and 13 years and 7 months, respectively. She had been 'slow' in school with signs of attention deficit and impaired fine motor skills. She also had temper tantrums and could be aggressive during such outbursts. She had received intensive support from her family and then completed basic secondary school. At 17 years, she was referred for obesity, hirsutism and menstrual irregularity. Hormones assay and pelvic ultrasound indicated polycystic ovary syndrome. Her weight was 90.8 kg and height 163.5 cm. She complained of pain and swelling of the wrists, the ankles and the knees. Despite extensive evaluation, the aetiology of those pains could not be identified. At the last evaluation, she was 23 years of age. Her weight was 108 kg (>97th centile), height 164.4 cm, BMI 40.2 and OFC 60 cm (>97th centile). Facial features include a high forehead with bilateral temporal retraction, long face, malar hypoplasia, triangular and massive chin, long nose ( Table 1 and figure 1). She was expecting a job in a sheltered environment because of her slowness and her lack of autonomy.
Proband 2 was the fourth child of unrelated French parents. Mother's height was 154 cm and father's height was 174 cm. He was born at term, and birth parameters were 51 cm (length), 3600 g (weight) and 36 cm (OFC). He was able to walk at 12 months of age, but speech delay was noted and had school difficulties. He was followed for Hashimoto's thyroiditis also known in her mother and maternal grandmother. Puberty began at around 12 years, along with an excessive weight gain. He was first seen at the genetic clinic at 14 years of age for developmental delay with stature and weight advance. Weight was 78.5 kg (+4 SD), height 174.5 cm (+2.8 SD) and head circumference 60 cm (+4 SD). Minor facial features were noted including a long face ( Table 1 and figure 1). He had slurred speech and was slow in speech and gestures. He had an accelerated carpal osseous maturation (15 at 14 years of age). Array CGH analysis was normal as well fragile-X research. At the last evaluation, he was 26 years old. Weight was 94 kg (+4.5 SD), height 177 cm (+0.5 SD) and OFC 62 cm (+4 SD). He had multiple nevi, marked hirsutism in the back, mild facial features (long face, pointed chin), astigmatism and behavioural troubles characterised by shyness and low sociability. He was still extremely slow in the daily life. He was poorly performing at school and had then difficulties to find work.
Results
Two heterozygous mutations in the SETD2 gene were identified in two patients with 'Sotos-like' syndrome. In proband 1, we identified a heterozygous c.820C>T (p.Gln274*) nonsense variant in the SETD2 gene ((Su(var)3–9, enhancer of zeste (E(z)) and trithorax (trx)) domain-containing protein 2) (MIM 612778) (RefSeq NM_014159.6). We also identified a heterozygous missense variant c.5444T>G (p.Leu1815Trp) in SETD2 in proband 2. None of the two variants were reported in dbSNP, the 1000 Genomes Project or in the Exome Variant Server. We confirmed the two mutations using Sanger sequencing. Proband 1 carrying a nonsense SETD2 mutation (c.820C>T; p.Gln274*) was adopted and her biological parents could not be tested. We confirmed that the SETD2 variant c.5444T>G (p.Leu1815Trp) found in proband 2 was not found in either of his parents, indicating that it was a de novo mutation (figure 1).
(Enlarge Image)
Figure 1.
Pedigree of the two patients with SETD2 mutations, supporting clinical features and confirmation by Sanger sequencing. Photos are published with the proxy consent of the parents and assent of the probands. Note the long face, slightly down-slanting palpebral fissures and pointed chin. The c.820C>T mutation (arrow) in proband 1 (adopted girl) and the de novo c.5444T>G mutation in proband 2 (arrow) were confirmed by Sanger sequencing.
Proband 1 was adopted when she was 4 months old. Her birth weight was 2850 g (25–50th centile), length was 50 cm (50th centile) and occipitofrontal circumference (OFC) was 34.5 cm (25–50th centile). Her development was considered as normal between 4 months and 3 years of age. She walked at the age of 14 months. Speech was slightly delayed. She was first seen at the genetic clinic at 7 years and 8 months of age for speech delay, overgrowth and overweight. Her weight was 75 kg (>97th centile), BMI was 23, height was 137 cm (>97th centile) and OFC was 57 cm (>97th centile). The clinical examination showed prominent forehead with high frontal hairline, downward slanting palpebral fissures, prominent mandible, long and large hands and feet. She had frequent ear and renal infections without any associated malformations. Ophthalmological evaluation, EEG, metabolic screen in blood and urine, endocrinologic screen were all normal. At 7 years and 8 months, CT scan showed mild ventricular dilatation. Her full-scale IQ score was 91, with a verbal IQ of 99 and a performance IQ of 80. Chromosome analysis showed a 46, XX karyotype, and CGH array gave a normal result. At a follow-up evaluation at 12 years and 2 months, weight was 84 kg (>97th centile), height 164 cm (>97th centile) and OFC was 60 cm. At 12 years and 2 months, MRI of the brain disclosed nodular and punctiform hypersignals at the anterior parts of corona radiate and in the centrum semi-ovale. Radiographs of lumbar and sacral vertebral column and pelvis were normal. Hand films revealed major advance in carpal and phalangeal bone age with a bone age of 10 years and 11 months then 16 years and 4 months at chronological ages of 7 years and 8 months and 13 years and 7 months, respectively. She had been 'slow' in school with signs of attention deficit and impaired fine motor skills. She also had temper tantrums and could be aggressive during such outbursts. She had received intensive support from her family and then completed basic secondary school. At 17 years, she was referred for obesity, hirsutism and menstrual irregularity. Hormones assay and pelvic ultrasound indicated polycystic ovary syndrome. Her weight was 90.8 kg and height 163.5 cm. She complained of pain and swelling of the wrists, the ankles and the knees. Despite extensive evaluation, the aetiology of those pains could not be identified. At the last evaluation, she was 23 years of age. Her weight was 108 kg (>97th centile), height 164.4 cm, BMI 40.2 and OFC 60 cm (>97th centile). Facial features include a high forehead with bilateral temporal retraction, long face, malar hypoplasia, triangular and massive chin, long nose ( Table 1 and figure 1). She was expecting a job in a sheltered environment because of her slowness and her lack of autonomy.
Proband 2 was the fourth child of unrelated French parents. Mother's height was 154 cm and father's height was 174 cm. He was born at term, and birth parameters were 51 cm (length), 3600 g (weight) and 36 cm (OFC). He was able to walk at 12 months of age, but speech delay was noted and had school difficulties. He was followed for Hashimoto's thyroiditis also known in her mother and maternal grandmother. Puberty began at around 12 years, along with an excessive weight gain. He was first seen at the genetic clinic at 14 years of age for developmental delay with stature and weight advance. Weight was 78.5 kg (+4 SD), height 174.5 cm (+2.8 SD) and head circumference 60 cm (+4 SD). Minor facial features were noted including a long face ( Table 1 and figure 1). He had slurred speech and was slow in speech and gestures. He had an accelerated carpal osseous maturation (15 at 14 years of age). Array CGH analysis was normal as well fragile-X research. At the last evaluation, he was 26 years old. Weight was 94 kg (+4.5 SD), height 177 cm (+0.5 SD) and OFC 62 cm (+4 SD). He had multiple nevi, marked hirsutism in the back, mild facial features (long face, pointed chin), astigmatism and behavioural troubles characterised by shyness and low sociability. He was still extremely slow in the daily life. He was poorly performing at school and had then difficulties to find work.
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