A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB) is caused by heterozygous mutation in the GNAI1 gene (139310) on chromosome 7q21.

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB) is characterized by global developmental delay apparent since infancy or early childhood, hypotonia with delayed motor development, impaired intellectual development with significant speech delay or absent speech, and variable behavioral abnormalities, such as autism, repetitive actions, or aggression. About two-thirds of patients have early-onset seizures that range from intractable to self-limiting. More variable features include nonspecific dysmorphic facial features, distal skeletal anomalies, and brain imaging abnormalities. The phenotypic manifestations and severity are highly variable (Muir et al., 2021).

Through exome sequencing of thousands of individuals with developmental delay, the Deciphering Developmental Disorders Study (2017) identified 8 unrelated individuals with de novo heterozygous mutations in the GNAI1 gene. These patients had global developmental delay with impaired intellectual development and poor or absent speech. More variable features included hypotonia, rare hypertonia, poor motor coordination, behavioral abnormalities, sleep disturbances, and hypoplasia of the cerebrum. Some patients had nonspecific dysmorphic facial features, including microcephaly or macrocephaly, abnormal facial shape, high forehead, downturned corners of the mouth, hypertelorism, deep-set eyes, epicanthus, heterochromia iridis, synophrys, anteverted nares, and tented upper lip. Common skeletal anomalies included tapered fingers, fifth finger clinodactyly, foot deformities, and joint hypermobility.

Muir et al. (2021) reported 24 unrelated patients, ranging from 3 to 18 years of age, with a neurodevelopmental disorder associated with de novo heterozygous mutations in the GNAI1 gene identified through exome sequencing. The patients were ascertained through international collaborative efforts, including the GeneMatcher Program. Thirteen of the patients (P2, P3, P7-P11, P14, P16, P18-20, and P24) had previously been reported (see, e.g., the Deciphering Developmental Disorders Study, 2017). All patients had global developmental delay ranging from mild (15%) to profound (55%). Speech was particularly affected, with language delays reported in 91% of individuals: 16 patients were nonverbal, including P5 who was 16 years old and P24 who was 18 years old. Hypotonia was common, and motor skills such as sitting and walking were delayed in most patients. Nine patients were nonambulatory, including P22 who was 14 years old and P24 who was 18. Rare patients had hypertonia or spasticity. Behavioral problems, including aggression, temper tantrums, hypersensitivity, impulsivity, and hand stereotypies were observed in the majority of patients. Seven were diagnosed with autism. Seventeen patients (74%) had seizures that were highly variable in severity and type, including absence, focal, myoclonic, and generalized tonic-clonic. Most had onset of seizures in infancy, and the response to treatment varied. Nonspecific brain imaging abnormalities were observed in about a third of patients: these included global cerebral atrophy, enlarged ventricles, delayed myelination, and choroid plexus or arachnoid cysts. One patient had bilateral mesotemporal sclerosis. However, brain imaging was normal in a significant number of individuals. About two-thirds (76%) of patients had dysmorphic features, although there was not a common gestalt. Features included brachycephaly, plagiocephaly, macrocephaly, round face, broad forehead, downslanting palpebral fissures, broad nose, short upturned nose, flat midface, maxillary hypoplasia, thick eyebrows, synophrys, short philtrum, hypotonic open mouth, thin or tented upper lip, and prominent lower lip. Skeletal defects included small hands and feet, tapered fingers, short fifth digits, clinodactyly, camptodactyly, long halluces, wide feet, foot deformities, and scoliosis. Less common features included feeding difficulties (9 patients), hyperphagia with obesity (7 patients), constipation, and cryptorchidism.

Wayhelova et al. (2022) reported a pair of 15-year-old monozygotic twin boys with a neurodevelopmental disorder. The twins were born by C-section at 29 weeks' gestation and were in the neonatology unit for 6 weeks. They had global developmental delay with walking at around 21 months, impaired intellectual development, severe dysphasia with very poor speech with only a few syllables, and cerebral palsy with clumsy motor skills. The boys were able to attend a specialized school; they had no apparent facial abnormalities, no seizures, and normal brain imaging. Twin B was diagnosed with acute lymphoblastic leukemia at age 5, which was in remission after chemotherapy.

Most of the heterozygous mutations in the GNAI1 gene that were identified in patients with NEDHISB by Muir et al. (2021) occurred de novo. One was inherited from an unaffected parent who was mosaic for the mutation.

In 8 unrelated patients with NEDHISB, the Deciphering Developmental Disorders Study (2017) identified de novo heterozygous mutations in the GNAI1 gene (see, e.g., 139310.0001). There were 5 missense mutations and 3 in-frame intragenic deletions. The patients were ascertained from large cohorts of thousands of individuals with developmental delay who underwent exome sequencing. Functional studies of the variants were not performed.

In 24 unrelated patients with NEDHISB, Muir et al. (2021) identified 16 different heterozygous mutations in the GNAI1 gene (see, e.g., 139310.0001-139310.0005). The patients were ascertained through international collaboration after exome sequencing identified the mutations. Thirteen of the patients had previously been reported (see, e.g., Deciphering Developmental Disorders Study, 2017). There were 12 missense mutations, 3 small in-frame deletions, and 1 frameshift mutation; none were present in the gnomAD database. The frameshift mutation was predicted to escape nonsense-mediated mRNA decay as it occurred in the penultimate exon. The mutations occurred de novo in all except 1 patient who inherited it from an unaffected mosaic mother. Although functional studies of the variants were not performed, structural modeling predicted that most would affect guanine nucleotide (GDP and GTP) binding motifs in GAI1 and disrupt proper GAI1 function. There were no obvious genotype/phenotype correlations.

In a pair of monozygotic twin boys with NEDHISB, Wayhelova et al. (2022) identified a de novo heterozygous missense mutation in the GNAI1 gene (D272G; 139310.0006). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; it was classified as pathogenic according to ACMG criteria. Functional studies of the variant were not performed. The authors noted that the GNAI1 gene is expressed in multiple fetal and postnatal brain structures and that disruption of gene function may lead to impaired neural development.