Al-Raqad Syndrome

A number sign (#) is used with this entry because of evidence that Al-Raqad syndrome (ARS) is caused by homozygous or compound heterozygous mutation in the DCPS gene (610534) on chromosome 11q24.

Clinical Features

Ng et al. (2015) reported a consanguineous Jordanian kindred in which 3 boys had significantly delayed psychomotor development, microcephaly, congenital hypotonia, and severe growth delay. Mild dysmorphic facial features included flat face, deep-set eyes, low-set ears with simple helices, and small nose and mouth. Additional features included joint laxity, brachydactyly, sandal gap, skin hypopigmentation, and atrial septal defects. Brain imaging was normal.

Ahmed et al. (2015) reported a consanguineous Pakistani family in which 3 individuals had delayed psychomotor development with moderate to severe intellectual disability with poor or absent speech. No dysmorphic facial features were clearly apparent, but 2 patients may have had a prominent upper jaw. One patient, who was born prematurely at 28 weeks' gestation, had microcephaly and severely delayed motor development with hypotonia and inability to walk. Brain imaging of 1 patient was normal. No abnormalities of skin, hair, joints, vision, or hearing were found.

Alesi et al. (2018) reported a 2-year-old girl, born to apparently nonconsanguineous Caucasian healthy parents who come from a small village in Italy, with a mutation in the DCPS gene. The patient was born at term from a dichorionic twin pregnancy; the cotwin was healthy. Birth height, weight, and head circumference were all below the 3rd centile. Her postnatal course was characterized by respiratory distress, requiring 2 months of intensive care hospitalization. Her early course was also complicated by an atrial septal defect, enteral feeding intolerance requiring parenteral nutrition, recurrent respiratory infections, and sleep apnea. At 26 months of age, all growth parameters were much lower than the 3rd centile. Other findings included psychomotor delay, reduced subcutaneous tissue, and hypotrophic muscle mass. Axial hypotonia with lower-limb hypertonia was also present. Clinical evaluation showed deep-set eyes, upslanting palpebral fissures, long philtrum, small mouth with thin upper lip, micrognathia, low-set ears, short neck, brachydactyly, fifth finger clinodactyly, blond hair, and pigmentary skin anomalies consisting of hypochromic patches alternating with normal skin, distributed along Blaschko lines.

Inheritance

The transmission pattern of Al-Raqad syndrome in the family reported by Ng et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 affected boys from a consanguineous Jordanian family with Al-Raqad syndrome, Ng et al. (2015) identified a homozygous splice site mutation in the DCPS gene (610534.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies showed that the mutation resulted in loss of enzyme function, which Ng et al. (2015) postulated would have an adverse effect on cell function, particularly in neurons.

In 2 members of a highly consanguineous Pakistani family with ARS presenting as nonsyndromic intellectual disability, Ahmed et al. (2015) identified a homozygous mutation in the DCPS gene (610534.0002). The mutation was found by homozygosity mapping and exome sequencing. A similarly affected child in another branch of this family was found to be compound heterozygous for that mutation and another DCPS mutation (610534.0003). In vitro functional expression studies and studies of patient cells showed absence of the wildtype protein and almost complete ablation of decapping activity compared to wildtype, consistent with a loss of function, although Ahmed et al. (2015) postulated a hypomorphic effect.

In a 2-year-old Italian girl with Al-Raqad syndrome, Alesi et al. (2018) identified a homozygous missense mutation in the DCPS gene (T87M; 610534.0004). The mutation, which was identified by SNP array analysis and direct Sanger sequencing, was present in heterozygous state in her parents and healthy cotwin.