A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (NEDHLSS) is caused by heterozygous missense mutation in the CACNA1C gene (114205) on chromosome 12p13.

Individuals with truncating variants in the CACNA1C gene have also been described; see below.

Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (NEDHLSS) is characterized by global developmental delay apparent from infancy. Affected individuals show severe hypotonia with delayed walking or inability to walk, poor or absent speech, and impaired intellectual development with behavioral abnormalities. Most patients have early-onset seizures, mild skeletal defects that are usually distal, and nonspecific dysmorphic features. More severely affected individuals have additional congenital abnormalities; however, cardiac involvement is rare (summary by Rodan et al., 2021).

Kosaki et al. (2018) reported a 5-year-old Japanese girl with postnatal growth failure, developmental delay, joint contractures, and cutaneous syndactyly. She had spells of loss of consciousness as well as some convulsions thought to be seizures, but these episodes were later attributed to pulmonary hypertension. At age 5 years, she was able to crawl and make eye contact; she had no meaningful words. Dysmorphic features included round face, frontal bossing, narrow mouth, low-set ears, depressed nasal bridge, thin upper lip, and thin scalp hair. She did not have prolongation of the QT interval.

Bozarth et al. (2018) reported an 18-month-old girl, born of unrelated parents, with poor overall growth, feeding difficulties, and dysmorphic features, including micrognathia, downturned corners of the mouth, frontal bossing, scant hair, and inverted nipples. She had multiple congenital anomalies, including laryngomalacia, gastroesophageal reflux, constipation, anal stenosis, and optic nerve hypoplasia with inability to track visually. Distal skeletal defects included clubfeet, finger and toe syndactyly, and camptodactyly. She had severe hypotonia and made almost no developmental progress; she required a feeding tube. Other features included disturbed sleep cycle and onset of various types of refractory seizures soon after birth. Brain imaging and cardiac workup were normal.

Rodan et al. (2021) reported 14 unrelated patients (P1-P14) with a neurodevelopmental disorder associated with de novo heterozygous nontruncating mutations (13 missense and 1 in-frame deletion) in the CACNA1C gene. The patients were ascertained through the GeneMatcher Program after exome sequencing identified the mutations. The patients, who ranged in age from 10 months to 24 years, had global developmental delay with hypotonia, motor delay, and variably impaired intellectual development, although more than half were noted to be severely affected. Nine patients were nonverbal and 6 who were old enough to walk were nonambulatory. The others showed mildly delayed walking, sometimes with an unsteady gait. Two individuals (P2 and P3) were noted to have learning disabilities and dyslexia, suggesting milder cognitive impairment. More than half had behavioral problems, most commonly stereotypic behaviors, abnormal social development, and aggression. All 11 patients from whom information was available developed seizures between 2 months and 8 years of age. Seizure types included focal, absence, generalized tonic-clonic, myoclonic, fever-sensitive seizures, and infantile spasms; 2 patients had West syndrome. EEG showed variable abnormalities, including focal, multifocal, or generalized discharges, spike and polyspike-and-wave discharges, and diffuse paroxysmal activity; 1 patient showed hypsarrhythmia. The seizures were refractory in some patients, but could be managed in others. Brain imaging was essentially normal. Most patients had distal skeletal defects, including joint hypermobility, foot deformities, hip dysplasia or dislocation, kyphoscoliosis, tapering fingers, adducted thumbs, and finger or toe syndactyly. About half of the patients had nonspecific dysmorphic features, such as high-arched palate, abnormal ears, or deep-set eyes, and many had ocular anomalies, including myopia, hyperopia, astigmatism, strabismus, and esotropia; 1 had cortical visual impairment. Cardiac involvement was not present in the majority of patients, but a few had variable findings: P13 had a prolonged QT interval, P14 had a borderline QT interval, P12 had possible ventricular conduction delay with trace valvular regurgitation, and P4 had a small atrial septal defect.

Individuals with Heterozygous Truncating Variants

Rodan et al. (2021) reported 11 individuals (P15-P22C) from 8 unrelated families with variable neurologic deficits associated with heterozygous truncating variants in the CACNA1C gene identified through exome sequencing. The individuals were identified through the GeneMatcher Program. The individuals had essentially normal early motor development and achieved ambulation, but almost all had expressive language delay. Cognition ranged from normal to moderately impaired. Most had behavioral abnormalities, including autism (in 5), ADHD, anxiety, shyness, social problems, echolalia, aggression, and emotional lability. Less common features included hypotonia, poor balance, tremor, paroxysmal movement disorders, minor dysmorphic features, and recurrent infections. One individual had transient seizures. None had cardiac involvement. In 3 families, the mutation was paternally inherited with variable penetrance and expressivity.

The heterozygous nontruncating mutations in the CACNA1C gene that were identified in patients with NEDHLSS by Rodan et al. (2021) occurred de novo.

In a 5-year-old Japanese girl with NEDHLSS, Kosaki et al. (2018) identified a de novo heterozygous missense variant in exon 24 of the CACNA1C gene (R1024G). The variant was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.

In an 18-month-old girl, born of unrelated parents, with NEDHLSS, Bozarth et al. (2018) identified a de novo heterozygous missense mutation in the CACNA1C gene (V1363M; 114205.0011). The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed.

In 14 unrelated patients (P1-P14) with NEDHLSS, Rodan et al. (2021) identified de novo heterozygous nontruncating mutations (13 missense and 1 in-frame deletion) in the CACNA1C gene (see, e.g., L614P, 114205.0012; L657F, 114205.0013; and L1408V, 114205.0014). The mutations, which were found by exome sequencing, were not present in the gnomAD database. The patients were ascertained through the GeneMatcher Program after exome sequencing was performed. Electrophysiologic patch-clamp voltage studies in HEK293 cells transfected with a subset of the mutations showed no or variable effects on the channel current, both increased and decreased. The authors noted that their studies used the canonical transcript, but that the CACNA1C gene undergoes extensive splicing and interacts with multiple accessory subunits. They postulated a dominant-negative effect rather than haploinsufficiency.

Heterozygous Truncating Variants

Rodan et al. (2021) identified heterozygous putative truncating mutations in the CACNA1C gene in 11 individuals (P15-P22C) from 8 unrelated families with variable neurologic deficits. The phenotype was not as severe as in those with missense mutations. In 3 families with truncating variants, the variant was paternally inherited with variable penetrance and expressivity. Variants occurred de novo in the other individuals. The variants (nonsense, frameshift, and splice site) occurred throughout the gene; all were predicted to result in premature termination and all but one were predicted to trigger nonsense-mediated mRNA decay. None of the variants were present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The authors postulated haploinsufficiency as a possible pathogenetic mechanism, but noted that this gene undergoes complex alternative splicing, which presents a challenge in interpreting the effect of the variants.

Among 25 individuals from 22 families with heterozygous variants in the CACNA1C gene, Rodan et al. (2021) found that the neurologic phenotype associated with de novo nontruncating variants was more severe than that associated with de novo or inherited truncating variants. The pathogenetic mechanism was difficult to determine due to the extensive alternative splicing of CACNA1C, but could result in a dominant-negative effect or haploinsufficiency.