SNOMEDCT: 1300117002; ORPHA: 597738;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.31 | Luscan-Lumish syndrome | 616831 | Autosomal dominant | 3 | SETD2 | 612778 |
A number sign (#) is used with this entry because of evidence that Luscan-Lumish syndrome (LLS) is caused by heterozygous mutation in the SETD2 gene (612778) on chromosome 3p21.
Luscan-Lumish syndrome (LLS) is characterized by macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures (Luscan et al., 2014; Lumish et al., 2015)
Luscan et al. (2014) described 2 unrelated individuals with similar clinical features including postnatal overgrowth, macrocephaly, obesity, speech delay, and advanced carpal ossification. The patients also had long and large hands and feet. Facial features included prominent forehead with high frontal hairline, downward slanting palpebral fissures, long nose, long face, malar hypoplasia, and prominent mandible. CT scan showed mild ventricular dilatation in 1 patient; MRI of the brain in this patient disclosed nodular and punctiform hypersignals at the anterior parts of the corona radiate and in the centrum semi-ovals. Behavioral difficulties were characterized by attention deficit, temper tantrums, aggressiveness, shyness, and low sociability, leading to problems in schooling and employment.
Lumish et al. (2015) reported a 17-year-old girl with autism spectrum disorder (ASD), developmental delay, intellectual disability, behavioral compulsions, aggressiveness, anxiety disorder, attention deficit-hyperactivity disorder, generalized tonic-clonic seizures starting at 10 years of age, Chiari I malformation, mild to moderate hydrocephalus of the third and lateral ventricles, progressive macrocephaly, syringomyelia, and short stature. Lumish et al. (2015) also stated that a patient, previously reported to have ASD by O'Roak et al. (2012, 2012), had a history of failure to thrive, nonfebrile seizures starting at 4 years of age, motor delays, low-normal nonverbal IQ, and macrocephaly.
Van Rij et al. (2018) described 2 patients with Luscan-Lumish syndrome. The first patient, a 4.5-year-old boy, had macrocephaly, speech and motor delay, autistic behavior, undescended testes, recurrent otitis media, and dysmorphic features including frontal bossing, high frontal hair line, occipital nevus flammeus, mild ptosis, soft elastic skin, and hyperlaxity of multiple joints. A hand X-ray showed delayed bone age. MRI of the brain was normal. The second patient, a 23-year-old woman, had macrocephaly, severely delayed speech and language development, mildly delayed motor skills, autism spectrum disorder, and behavioral issues including aggressive outbursts and self-mutilating behavior, with a high pain threshold. Dysmorphic features included asymmetric face with broad forehead, broad and high nasal bridge, large and broad chin, high palate, and tongue with deep creases. She also had recurrent otitis media and nasal polyps that required removal 3 times. MRI of the brain showed a slightly thickened corpus callosum but was otherwise normal. She also had truncal obesity with a body mass index of 32.3.
Marzin et al. (2019) reported 4 patients with Luscan-Lumish syndrome and reviewed the 9 previously reported patients. Over 90% of patients had macrocephaly, with advanced stature and obesity in half the cases. Intellectual disability was seen in 83%, autism spectrum disorders in 89%, and behavioral difficulties in 100% with aggressive outbursts in 83%. Other features included joint hypermobility (29%), hirsutism (33%), and nevi (50%).
Chen et al. (2021) reported 2 patients with autism spectrum disorder and features of Luscan-Lumish syndrome and reviewed data on 14 previously reported patients. Intellectual disability was reported in 7/7 patients, speech delay in 11/12, tall stature in 7/12, motor delay in 8/12, and autism spectrum disorder in 8/14. Behavioral issues such as ADHD, aggressive behavior, and anxiety were also reported. Recurrent otitis media was reported in 5 patients, and accelerated osseous maturation was reported in 4 patients.
The heterozygous mutations in the SETD2 gene that were identified in 2 patients with LLS by Luscan et al. (2014) and Lumish et al. (2015), respectively, occurred de novo. Familial segregation of the mutation in a third patient, studied by Luscan et al. (2014), could not be determined because the patient had been adopted.
O'Roak et al. (2012, 2012) sequenced the exomes of parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. They also sequenced the exomes of 50 unaffected sibs corresponding to 31 of the new and 19 of the previously reported trios, for a total of 677 individual exomes from 209 families. All of the families were from the ASD Simmons Simplex Collection (SSC). The authors identified 4 individuals with ASD and heterozygous mutations in the SETD2 gene: 2 with nonsense mutations (paternally-inherited C94X and maternally-inherited Q7X), 1 with a de novo I41F missense mutation, and 1 (patient 12565.p1) with a de novo frameshift mutation. Lumish et al. (2015) stated that the patient with the frameshift mutation (612778.0001) also had a history of failure to thrive, nonfebrile seizures starting at 4 years of age, motor delays, low-normal nonverbal IQ, and macrocephaly.
Iossifov et al. (2014) sequenced exomes from more than 2,500 simplex families, each having a child with ASD, and identified 2 patients with a heterozygous mutation in the SETD2 gene: a 1-basepair deletion and a missense mutation. Most of the families were from the SSC.
Luscan et al. (2014) analyzed the coding sequences of 14 H3K27 methylation-related genes and 8 H3K36 methylation-related genes using a targeted next-generation sequencing approach in 3 Sotos (see 117550), 11 'Sotos-like,' and 2 Weaver (277590) syndrome patients and identified heterozygous mutations in the SETD2 gene in 2 patients with a 'Sotos-like' syndrome (612778.0002 and 612778.0003). Neither variant was reported in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
By whole-exome sequencing in a 17-year-old girl with Luscan-Lumish syndrome, Lumish et al. (2015) identified a heterozygous de novo frameshift mutation in the SETD2 gene. The variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project database, in the dbSNP database, or in over 9,000 clinical exomes sequenced at GeneDx.
In 2 patients with intellectual disability, speech delay, autism spectrum disorder, and macrocephaly consistent with Luscan-Lumish syndrome, van Rij et al. (2018) identified de novo heterozygous frameshift mutations in the SETD2 gene. These included a deletion/insertion (c.1647_1667delinsAC) in exon 3 and a single basepair deletion (c.6775delG) in exon 15, both resulting in a frameshift and a premature stop codon. The variants were not present in the unaffected parents of either patient.
In 4 patients with Luscan-Lumish syndrome, Marzin et al. (2019) identified 2 nonsense mutations (K1426X and Y2157X) and 2 missense mutations (Y1666C and R1625H) in the SETD2 gene, all of which were located in the catalytic domain SET2. In a review of their 4 patients and 9 previously reported patients with LLS, the authors found that the mutations were intragenic loss-of-function variants (69% truncating and 31% missense) distributed throughout the gene.
Using targeting sequencing in 2 patients with autism spectrum disorder and other features of Luscan-Lumish syndrome, Chen et al. (2021) identified 2 de novo mutations in the SETD2 gene (NM_014159): a splicing mutation (c.4715+1G-A) and a missense mutation (c.3185C-T, P1062L). Neither variant was reported in large public databases. The authors also evaluated 17 reported de novo SETD2 variants (8 frameshift, 1 nonsense, 7 missense, 1 in-frame deletion). All missense variants occurred at residues that were evolutionarily conserved. Using ACMG criteria, 13 of the 19 variants were classified as pathogenic, 5 as likely pathogenic, and one (missense) as a variant of uncertain significance.
Chen, M., Quan, Y., Duan, G., Wu, H., Bai, T., Wang, Y., Zhou, S., Ou, J., Shen, Y., Hu, Z., Xia, K., Guo, H. Mutation pattern and genotype-phenotype correlations of SETD2 in neurodevelopmental disorders. Europ. J. Med. Genet. 64: 104200, 2021. [PubMed: 33766796] [Full Text: https://doi.org/10.1016/j.ejmg.2021.104200]
Iossifov, I., O'Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Vives, L., Patterson, K. E., Smith, J. D., Paeper, B., and 35 others. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515: 216-221, 2014. [PubMed: 25363768] [Full Text: https://doi.org/10.1038/nature13908]
Lumish, H. S., Wynn, J., Devinsky, O., Chung, W. K. SETD2 mutation in a child with autism, intellectual disabilities and epilepsy. J. Autism Dev. Disord. 45: 3764-3770, 2015. [PubMed: 26084711] [Full Text: https://doi.org/10.1007/s10803-015-2484-8]
Luscan, A., Laurendeau, I., Malan, V., Francannet, C., Odent, S., Giuliano, F., Lacombe, D., Touraine, R., Vidaud, M., Pasmant, E., Cormier-Daire, V. Mutations in SETD2 cause a novel overgrowth condition. J. Med. Genet. 51: 512-517, 2014. [PubMed: 24852293] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102402]
Marzin, P., Rondeau, S., Aldinger, K. A., Alessandri, J. L., Isidor, B., Heron, D., Keren, B., Dobyns, W. B., Cormier-Daire, V. SETD2 related overgrowth syndrome: presentation of four new patients and review of the literature. Am. J. Med. Genet. 181C: 509-518, 2019. [PubMed: 31643139] [Full Text: https://doi.org/10.1002/ajmg.c.31746]
O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338: 1619-1622, 2012. [PubMed: 23160955] [Full Text: https://doi.org/10.1126/science.1227764]
O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., Turner, E. H., Stanaway, I. B., and 11 others. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246-250, 2012. [PubMed: 22495309] [Full Text: https://doi.org/10.1038/nature10989]
van Rij, M. C., Hollink, I. H. I. M., Terhal, P. A., Kant, S. G., Ruivenkamp, C., van Haeringen, A., Kievit, J. A., van Belzen, M. J. Two novel cases expanding the phenotype of SETD2-related overgrowth syndrome. Am. J. Med. Genet. 176A: 1212-1215, 2018. [PubMed: 29681085] [Full Text: https://doi.org/10.1002/ajmg.a.38666]