Mental Retardation, X-Linked, Syndromic, 35

A number sign (#) is used with this entry because of evidence that X-linked syndromic mental retardation-35 (MRXS35) is caused by mutation in the RPL10 gene (312173) on chromosome Xq28.

Clinical Features

Brooks et al. (2014) reported a family in which 3 males spanning 2 generations had a syndromic form of mental retardation. The 4.5-year-old proband was born at 35 weeks' gestation due to polyhydramnios; his 2 affected maternal uncles were born at 38 and 37 weeks', respectively. The patients had dysmorphic facial features, including prognathism, with dental crowding or thin upper lip; 1 had protuberant ears. All had progressive microcephaly (up to -9.6 SD), seizures, hypotonia, gastroesophageal reflux disease with severe growth retardation, and genitourinary abnormalities, namely cryptorchidism and/or hypospadias. The 2 uncles had cardiac septal defects and developed hearing loss. Other more variable features included tapered fingers, camptodactyly, toe syndactyly, and recurrent infections in childhood. The 2 uncles were essentially nonverbal and minimally or nonambulatory as young adults. None of the patients had anemia.

Thevenon et al. (2015) reported a family with MRXS35. The clinical features of 4 male patients were described. The patients tended to have early delivery (35 to 38 weeks' gestation), usually due to excess amniotic fluid. They all had delayed psychomotor development with hypotonia, delayed speech acquisition, and mild microcephaly (-2 SD). The proband was described as having dysmorphic features, including prominent ears, broad nasal bridge, epicanthus, and small mouth. He had a stocky build, single palmar creases, short fingers, clinodactyly, and cutaneous syndactyly of the toes. Similar features were observed in the other patients. Two patients had single febrile seizures in infancy. Three patients had moderate to severe myopia, 2 had ataxia/cerebellar syndrome, 2 had cryptorchidism, and 1 had small testes. None had behavioral problems, and hearing was normal.

Zanni et al. (2015) reported a family in which 2 adult male first cousins from Italy had MRXS35. The proband had intrauterine growth retardation, neonatal hypotonia, delayed psychomotor development, and overall growth retardation. Both patients had delayed walking at age 4 years with ataxic gait, and both had minor dysmorphic features, such as dolichocephaly, long and flat philtrum, microretrognathia, and protruding ears. Skeletal radiographic studies showed spondyloepiphyseal dysplasia, scoliosis, and osteoporosis, and brain imaging showed cerebellar hypoplasia. Additional features in the proband included retinitis pigmentosa, inguinal hernia, renal tubulopathy, and central hypothyroidism; these features were not found in his cousin, who had hypermetropia and cryptogenic focal epilepsy that was treated with medication.

Inheritance

The transmission pattern of MRXS35 in the family reported by Brooks et al. (2014) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 3 members of a family with MRXS35, Brooks et al. (2014) identified a hemizygous missense mutation in the RPL10 gene (K78E; 312173.0003). The mutation, which was found by sequencing of an X-linked gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. Carrier females showed fully skewed X inactivation of the mutation-bearing X chromosomes.

In 4 male members of a family with MRXS35, Thevenon et al. (2015) identified a hemizygous missense mutation in the RPL10 gene (G161S; 312173.0004). The mutation, which was found by exome sequencing and segregated with the disorder in the family. Carrier females showed fully skewed X inactivation of the mutation-bearing X chromosome. Functional studies of the variant and studies of patient cells were not performed.

In 2 male first cousins from Italy with MRXS35, Zanni et al. (2015) identified identified a hemizygous missense mutation in the RPL10 gene (A64V; 312173.0005). The mutation, which was found by X-chromosome exome sequencing, was confirmed by Sanger sequencing and filtered against public databases. It segregated with the disorder in the family. Carrier females showed fully skewed X inactivation. Studies in yeast showed that the A64V mutant protein was functional and able to restore temperature-sensitive growth and translational defects. Ribosomal profile analysis showed that the A64V mutation was associated with a reduction in a large mutant 80S peak, indicating a reduction in translation initiation, with an increase in polysomes, indicating an increase in translationally active ribosomes. Of note, the patients had spondyloepiphyseal dysplasia.

Animal Model

Brooks et al. (2014) found that rpl10 had enriched expression in the anterior compared to posterior structures in zebrafish embryos. Expression was particularly evident at the midbrain-hindbrain boundary. Morpholino knockdown of the rpl10 gene in Zebrafish embryos resulted in microcephaly with a significant decrease in head size, but not in body length. The microcephaly could by rescued with injection of wildtype human RPL10, but not with mutant K78E RPL10, suggesting that the K78E variant is functionally null. Morphant head structures showed decreased protein translation activity compared to wildtype, but morphant body structures did not show these defects, suggesting that rpl10 expression is spatiotemporally regulated. Morphant brains showed increased apoptosis compared to controls, suggesting that this is the mechanistic drive of microcephaly in the embryos.