Short Stature, Brachydactyly, Intellectual Developmental Disability, And Seizures

A number sign (#) is used with this entry because of evidence that short stature, brachydactyly, intellectual developmental disability, and seizures (SBIDDS) is caused by compound heterozygous mutation in the PRMT7 gene (610087) on chromosome 16q22.

Clinical Features

Akawi et al. (2015) reported 6 females, ranging in age from 6 to 23 years, from 3 unrelated families with global delayed development associated with skeletal abnormalities. Walking was achieved between 2 and 5 years of age, and all had learning disabilities or mild intellectual disabilities with delayed speech development. The patients had short stature (-1.4 to -2.9 SD), obesity, brachydactyly, and short metacarpals and metatarsals, reminiscent of Albright hereditary osteodystrophy (AHO; see 103580). Two sisters had pseudohypoparathyroidism, but 1 woman from a second family had normal serum calcium, phosphate, and parathyroid levels; one of 3 sisters from a third family was reported to have 'no definite [endocrine] anomalies' whereas the other 2 sisters were not assessed for these parameters. Four patients had mild seizures, either partial or absence, that were well-controlled, and most had hypotonia. Variable dysmorphic features included microcephaly, epicanthal folds, short palpebral fissures, strabismus, astigmatism, wide or depressed nasal bridge, and short upturned nose.

Kernohan et al. (2017) reported an 8-year-old boy, born of consanguineous Afghan parents, with a phenotype similar to that described by Akawi et al. (2015). The patient had intrauterine growth retardation and showed microcephaly (-4 SD) and dysmorphic features at birth. He had a round head, short hairy forehead, hypoplasia of the supraorbital ridges, deep-set eyes, ptosis, infraorbital creases, flat nasal bridge with a broad nasal root and tip, anteverted nostrils, long philtrum, thin lips, high-arched palate, retrognathia, square chin, and short neck. Other features included laryngomalacia necessitating G-tube placement, cryptorchidism, small feet, and brachydactyly with webbing of some fingers. Brain imaging showed mildly delayed myelination that later normalized. He was also hypotonic with decreased muscle bulk. The boy had severe global developmental delay, developed seizures at age 4 years, began walking at age 6 years, remained incontinent, and had very poor expressive speech.

Inheritance

The transmission pattern of SBIDDS in the families reported by Akawi et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 females from 3 unrelated families with SBIDDS, Akawi et al. (2015) identified compound heterozygous mutations in the PRMT7 gene (610087.0001-610087.0005). The mutations, which were found by exome sequencing, segregated with the disorder in the families. The patients were part of a large study of 4,125 families with a variety of severe developmental disorders who underwent exome analysis. The mutations were predicted to result in a loss of function, but functional studies of the variants and studies of patient cells were not performed.

In a boy, born of consanguineous parents of Afghan descent, with SBIDDS, Kernohan et al. (2017) identified a homozygous 15,309-bp deletion encompassing the transcriptional start site of the PRMT7 gene (610087.0006). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient-derived cells showed complete absence of the PRMT7 protein and transcript, consistent with a loss of function. Analysis of patient cells showed decreased arginine methylation of target proteins, including certain core histone proteins such as H2B (see 609904) and H4 (see 602822). Patient cells also showed abnormal expression of genes within the Wnt signaling pathway. Parental cells showed decreased methylation levels compared to controls, consistent with haploinsufficiency.

Animal Model

Akawi et al. (2015) found that Prmt7-null mice had decreased viability (45% survival by day P14). Surviving mice showed increased fat mass, reduced length, limb bone anomalies, including shortened fifth metatarsals, and decreased bone mineral density and content. Some of the changes were more significant in females.