Mental Retardation, Autosomal Dominant 50

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-50 (MRD50) is caused by heterozygous mutation in the NAA15 gene (608000) on chromosome 4q31.

Clinical Features

Stessman et al. (2017) reported 13 unrelated patients with a variety of cognitive neurodevelopmental disorders associated with heterozygous variants in the NAA15 gene. Clinical details were limited since the patients were ascertained from large cohorts of DNA samples, but 10 of 11 (91%) had developmental delay/intellectual disability (DD/ID) that varied from mild to severe, 5 of 6 (83%) had delayed speech and language, and 5 of 8 (63%) had a formal diagnosis of autism spectrum disorder (ASD), although several other patients had autistic features. One of the patients was a 15-year-old boy diagnosed with Asperger syndrome. Two of 4 patients were noted to have motor delay. Other variable features included behavior problems, such as selective mutism or aggressive behavior, poor growth, and nonspecific dysmorphic features. None had seizures, and brain imaging, when performed, was normal. Three patients reportedly had a mother with mild intellectual disability.

Cheng et al. (2018) reported 39 individuals from 34 unrelated families with intellectual disability, autism spectrum disorder, and variable extraneurologic congenital anomalies associated with heterozygous likely gene disrupting (LGD) variants in the NAA15 gene (see MOLECULAR GENETICS). The cohort included the patients previously reported by Stessman et al. (2017). The phenotype was variable, but all patients had some degree of neurodevelopmental disability, including impaired motor abilities with mildly delayed walking, mild to moderate intellectual disability, impaired language development, and behavioral abnormalities, such as autism spectrum disorder, poor attention, and hyperactivity. Many had dysmorphic facial features, but there was no consistent pattern. Some patients had poor overall growth and some had short stature. Motor features included fine motor problems (12%) and hypotonia (14%). Other features included seizures (23%) and feeding difficulties (57%). Four patients had cardiac anomalies, one of whom had a complex heterotaxy syndrome. The patients were ascertained through international collaboration of research and clinical groups who shared whole-genome, whole-exome, or candidate gene sequencing results of patients with variable intellectual disability.

Inheritance

The transmission pattern MRD50 in 3 families reported by Cheng et al. (2018) was consistent with autosomal dominant inheritance. However, the majority of affected individuals carried a de novo heterozygous mutation in the NAA15 gene.

Molecular Genetics

In 13 unrelated patients with MRD50, Stessman et al. (2017) identified 13 different heterozygous variants in the NAA15 gene (see, e.g., 608000.0001-608000.0003). Ten of the variants were categorized as 'likely gene disruptive' (LGD) events, such as nonsense or frameshift variants, and 3 were missense variants predicted to be deleterious. Four of the variants, all of which were LGD, were demonstrated to occur de novo. One missense variant was paternally inherited without clinical information on the father, and parental DNA was not available for the other 8 patients to determine segregation. Ten of the variants were private, only identified in the affected patient (family), and 3 were classified as 'ultra-rare.' Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 11,730 patients with autism spectrum disorder, intellectual disability, and/or developmental delay involving 15 centers across 7 countries and 4 continents. The authors used single-molecule molecular inversion probes (smMIPs) to sequence 208 candidate genes in these patient samples and confirmed the findings by Sanger sequencing. The findings of de novo LGD mutations in the NAA15 gene was statistically significant. Using statistical analysis, Stessman et al. (2017) stated that given the incidence of developmental delay in the general population (5.12%), the penetrance of LGD NAA15 mutations was estimated to be 35.3%.

In 39 patients from 34 unrelated families with MRD50, including the patients previously reported by Stessman et al. (2017), Cheng et al. (2018) identified 25 heterozygous variants in the NAA15 gene (see, e.g., 608000.0004-608000.0007). Most of the mutations occurred de novo, although 3 families showed autosomal dominant inheritance of the mutations. All of the mutations were classified as LGD mutations, including nonsense, frameshift, and splice site mutations. The mutations occurred throughout the gene and were predicted or demonstrated to result in nonsense-mediated mRNA decay and a loss of protein function in cells derived from some of the patients. Expression of several of the mutations in NatA-null yeast failed to rescue growth defects, indicating that they caused a loss of function. Cheng et al. (2018) concluded that haploinsufficiency of NAA15 was the most likely mechanism for this variable neurodevelopmental disorder, although the possibility of a dominant-negative or gain-of-function mechanism could not be excluded. A few patients had previously been reported in other large cohort studies (Zaidi et al., 2013, Longoni et al., 2017).