A number sign (#) is used with this entry because of evidence that Alkuraya-Kucinskas syndrome (ALKKUCS) is caused by homozygous or compound heterozygous mutation in the KIAA1109 gene (611565) on chromosome 4q27.

ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures (summary by Gueneau et al., 2018).

Alazami et al. (2015) reported a fetus (family 13DG1900) with hydrocephalus, micrognathia, clubfeet, arthrogryposis with flexion deformity, pleural effusion, and Dandy-Walker malformation who died 1 hour after birth.

Gueneau et al. (2018) reported 13 individuals from 10 unrelated families with a severe neurodevelopmental disorder, including the fetus reported by Alazami et al. (2015), who was born of consanguineous Saudi parents. Among the 13 patients reported by Gueneau et al. (2018), only 3 patients from 2 families were alive at 7, 11, and 13 years of age. Seven patients died between birth and the first months of life, and 3 affected pregnancies were terminated due to detection of the condition on prenatal ultrasound. In addition, 3 families had a history of recurrent miscarriages. The 3 living children (2 Lithuanian sibs and a girl from the UK) had global developmental delay from infancy and variable intellectual disability. The least severely affected patient was an 11-year-old girl from the UK with behavioral problems and learning disabilities who was able to walk and attend school. Prenatal ultrasound showed severe microcephaly (-5 SD) and reduced white matter volume. She had dysmorphic features, including hypertelorism, upslanting palpebral fissures, and high-arched palate, as well as a complex congenital heart disorder with tetralogy of Fallot. The 2 Lithuanian sibs had severe intellectual disability with absent language and hypotonia resulting in inability to stand without support, as well as early-onset epilepsy, plagiocephaly, and cerebral parenchymal rarefaction and ventriculomegaly on brain imaging. These 3 children had eye movement abnormalities, including oculomotor apraxia, hypermetropia, and strabismus, as well as mild joint contractures and foot deformities. The more severely affected 10 deceased infants and fetuses showed abnormalities on prenatal ultrasound, mainly arthrogryposis with flexion deformities, edema, and abnormal brain imaging. The patients had joint contractures, adducted thumbs, camptodactyly, clinodactyly, clenched hands, clubfoot, and overlapping fingers and toes. There were variable dysmorphic features, including macrocephaly, hydrocephalus, hypotelorism, hypertelorism, small eyes, low-set ears, posteriorly rotated ears, short nose, flattened nasal bridge, anteverted nares, retrognathia, cataracts, cystic hygroma, and webbed neck. Pre- and postnatal brain imaging showed multiple variable severe abnormalities in all patients. Abnormalities included enlarged ventricles, hypoplasia or absence of the corpus callosum, cortical lamination or migration defects, thin parenchymal mantle, gyral abnormalities, lissencephaly, neuronal heterotopia, prominent germinal matrix, and brainstem and cerebellar hypoplasia or dysplasia, often with a kinked brainstem. Additional congenital abnormalities were variable, but included pericardial or pleural effusions, heart or kidney abnormalities, and scrotum or penis hypoplasia. The infants that were born had hypotonia and breathing difficulties.

The transmission pattern of ALKKUCS in the families reported by Gueneau et al. (2018) was consistent with autosomal recessive inheritance.

In a female infant, born of consanguineous Saudi parents, with ALKKUCS, Alazami et al. (2015) identified a homozygous nonsense mutation in the KIAA1109 gene (Y519X; 611565.0001). The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the variant were not performed.

In 12 patients from 9 unrelated families with ALKKUCS, Gueneau et al. (2018) identified homozygous or compound heterozygous mutations in the KIAA1109 gene (see, e.g., 611565.0002-611565.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available. Functional studies of the KIAA1109 variants and studies of patient cells were not performed, but Gueneau et al. (2018) noted that the only individuals who survived beyond infancy had biallelic missense mutations. Knockdown of the gene in zebrafish resulted in head defects and abnormal body curvature (see ANIMAL MODEL).

Verstreken et al. (2009) found that deletion of the KIAA1109 ortholog 'tweek' in Drosophila resulted in larval lethality. Rare homozygous flies that survived to adulthood were unable to walk or stand upright for long periods and exhibited seizures. The authors named the gene tweek after the cartoon character 'Tweek' from the television series 'South Park,' because the behavior of the adult mutant flies reminded them of the character. Tweek mutation resulted in NMJ synaptic vesicles that were reduced in number, but increased in size, with increased neurotransmitter release during spontaneous vesicle fusion events. The basal content of PI(4,5)P2 was reduced at tweek mutant NMJs, with altered PI(4,5)P2 distribution during neuronal activity and altered synaptic vesicle recycling.

Gueneau et al. (2018) noted that Kiaa1109-null mice show embryonic lethality, but that some Drosophila with complete loss of Kiaa1109 can survive; the surviving animals present with severe neurologic defects, such as seizures and inability to stand or walk (tweek phenotype). Gueneau et al. (2018) found that morpholino knockdown of the kiaa1109 gene in zebrafish resulted in increased frequency of hydrocephalus or other head defects and increased body curvature compared to controls. However, unlike in mice, homozygosity for disruption of the kiaa1109 gene did not appear to result in lethality.