Luscan-Lumish Syndrome

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.

Description

Luscan-Lumish syndrome 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)

Clinical Features

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.

Inheritance

The inheritance pattern of Luscan-Lumish syndrome is autosomal dominant (Luscan et al., 2014; Lumish et al., 2015).

Molecular Genetics

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 (612778.0004) 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.