A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures (NEDFSS), is caused by heterozygous mutation in the TRPM3 gene (608961) on chromosome 9q21.

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures (NEDFSS), is characterized by these features and global developmental delay with delayed or absent walking, moderate to severely impaired intellectual development, and poor or absent speech acquisition. Affected individuals may also have behavioral abnormalities. About half of patients develop various types of seizures that are usually well-controlled with medication. Rare patients are noted to have heat intolerance or insensitivity to pain (Lines et al., 2022).

Dyment et al. (2019) reported 7 unrelated patients, ranging from 6 to 38 years of age, with a similar neurodevelopmental disorder who were ascertained through the GeneMatcher database after exome sequencing identified a recurrent de novo heterozygous mutation in the TRPM3 gene (V837M; 608961.0001) in all patients. From infancy, they showed mild overall growth impairment and global developmental delay with hypotonia, delayed walking by around 5 years (2 patients were nonambulatory at 6 and 28 years of age), moderately to severely impaired intellectual development with poor or absent speech, and lack of toilet training in most. Four were noted to have autistic features. All had epilepsy and/or various types of seizures confirmed by EEG with onset in early childhood. Dysmorphic craniofacial features included broad forehead, deep-set eyes, bulbous nasal tip, long nose, short or long philtrum, strabismus, and micrognathia. Most patients had variable skeletal anomalies, including scoliosis, foot or finger deformities, hip dysplasia, plagiocephaly, and/or pectus excavatum. One had torticollis and another showed athetoid movements in infancy. Brain imaging showed cortical atrophy/enlarged ventricles in 2 patients, but was normal in the other patients.

De Sainte Agathe et al. (2020) reported a 5-year-old French girl with NEDFSS associated with the recurrent de novo heterozygous V837M mutation in the TRPM3 gene (608961.0001) identified through trio-based whole-exome sequencing. She presented with bilateral hip and patellar dislocations necessitating surgical intervention, and was also noted to have hypotonia, global developmental delay with walking at age 5 years, absent speech, and behavioral abnormalities, including aggression, high frustration, and stereotypies. Dysmorphic facial features included broad prominent forehead, synophrys, low-set ears, bulbous nasal tip, short philtrum, and short neck. She had a diminished pain threshold and her mother reported her to have heat intolerance. Additional features included dysarthria, dysphagia, and gastrointestinal reflux. Brain imaging showed mildly enlarged ventricles and nonspecific periventricular white matter hyperintensities. She did not have seizures and EEG studies were normal. Lines et al. (2022) reported follow-up of this patient, noting that she still had not developed seizures at 7.5 years of age.

Gauthier et al. (2021) reported a 7-year-old boy, born of unrelated parents of African and Portuguese origin, with NEDFSS associated with the recurrent de novo heterozygous V837M mutation in the TRPM3 gene. He presented in early childhood with axial hypotonia, global developmental delay with inability to walk and absent language, and behavioral abnormalities with autistic-like features, stereotypies, and temper tantrums. At age 7 years, he developed eye-blinking episodes and generalized tonic-clonic seizures. Brain imaging showed cerebellar atrophy and enlarged ventricles. Dysmorphic features included broad forehead, strabismus, low-set ears, prognathia, dental malocclusion, open mouth, and pectus excavatum. Other notable findings included trigonocephaly, macrocephaly, and decreased sensitivity to pain.

Lines et al. (2022) reported 7 unrelated patients, ranging from 5 months to 15 years of age, with NEDFSS associated with the recurrent de novo heterozygous V837M mutation in the TRPM3 gene who were ascertained through the GeneMatcher program. The patients showed congenital hypotonia, global developmental delay, delayed walking, and moderate to severe intellectual development with poor or absent speech, although 4 individuals were younger than 36 months of age. Only 2 patients had seizures in early childhood: 1 had a single febrile seizure and another had generalized tonic-clonic seizures that were well-controlled. However, EEG abnormalities were found in a total of 4 patients. Most patients had variable skeletal anomalies, including hip dysplasia, talipes equinovarus or other foot deformities, torticollis, tapering fingers, and scoliosis. Dysmorphic facial features were noted in all patients, although there was not a specific recognizable gestalt. These included brachycephaly, plagiocephaly, broad forehead, frontal bossing, midface hypoplasia, hypertelorism, strabismus, deep-set eyes, low-set ears, small mouth, downturned corners of the mouth,, and small or prominent chin. Brain imaging was normal in 2 individuals and showed nonspecific abnormalities in others, such as small brain, delayed myelination, enlarged ventricles, occipital arachnoid cyst, and thin corpus callosum. One patient had gray matter heterotopia.

The heterozygous mutations in the TRPM3 gene that were identified in patients with NEDFSS by Dyment et al. (2019) occurred de novo.

By trio-based exome sequencing in 7 unrelated patients with NEDFSS, Dyment et al. (2019) identified a recurrent de novo heterozygous missense mutation in the TRPM3 gene (V837M; 608961.0001). The mutation, which occurred in the highly conserved S4-S5 linker region of one of several reported protein isoforms, was not present in the gnomAD database. The substitution was proposed to produce a conformational change during gated channel opening and thus have functional significance. Functional studies of the variant and studies of patient cells were not performed. Dyment et al. (2019) also reported an 8-year-old girl (patient 8) with a similar disorder who carried a de novo heterozygous P937Q variant in the TRPM3 gene that was found once in the gnomAD database (frequency of 3.98 x 10(-6)). Patient 8 also carried a de novo heterozygous splice site variant in the DDB1 gene (600045) that was considered a variant of uncertain significance; de novo heterozygous mutations in the DDB1 gene cause a different neurodevelopmental disorder (619426).

In a 5-year-old French girl with NEDFSS, De Sainte Agathe et al. (2020) identified the recurrent de novo heterozygous V837M mutation in the TRPM3 gene through trio-based whole-exome sequencing. Functional studies were not performed.

By trio-based whole-exome sequencing of a 7-year-old boy with NEDFSS, Gauthier et al. (2021) identified the de novo recurrent V837M mutation in the TRPM3 gene. Functional studies of the variant were not performed.

Lines et al. (2022) identified the recurrent de novo heterozygous V837M mutation in 7 additional unrelated patients with NEDFSS identified through exome sequencing. Functional studies of the variant were not performed.

Variant Function

Zhao et al. (2020) performed in vitro functional expression studies of the V837M mutation (also known as V990M and V992M) and the P937Q variant (also known as P1090Q and P1092Q) in the TRPM3 gene in transfected Xenopus oocytes and HEK293 cells. They found that the disease-associated mutations render the TRPM3 channel overactive, possibly via different mechanisms, and the authors postulated that increased neuronal excitability and/or calcium-induced neuronal damage may underlie disease pathogenesis.

In HEK293 cells, Van Hoeymissen et al. (2020) found that TRPM3 variants V990M and P1090Q resulted in increased channel current densities compared to wildtype, both in the basal state and when stimulated by agonists. Their overall findings indicated that the mutations caused altered functional properties of the channel, and the authors hypothesized that increased calcium influx and depolarizing channel activity is the basis of seizure development and neurodevelopmental symptoms in patients carrying these mutations.