Expanding the phenotypic spectrum of MBOAT7‐related intellectual disability

Abstract

MBOAT7 gene pathogenic variants are a newly discovered and rare cause for intellectual disability, autism spectrum disorder (ASD), seizures, truncal hypotonia, appendicular hypertonia, and below average head sizes (ranging from −1 to −3 standard deviations).There have been only 16 individuals previously reported who have MBOAT7-related intellectual disability, all of whom were younger than 10 years old and from consanguineous relationships. Thus, there is a lack of phenotypic information for adolescent and adult individuals with this disorder. Medical genetics and psychiatric evaluations in a 14-year-old female patient with a history of global developmental delay, intellectual disability, overgrowth with macrocephaly, metrorrhagia, seizures, basal ganglia hyperintensities, nystagmus, strabismus with amblyopia, ASD, anxiety, attention deficit hyperactivity disorder (ADHD), aggressive outbursts, and hyperphagia included a karyotype, methylation polymerase chain reaction for Prader-Willi/Angelman syndrome, chromosome microarray, and whole exome sequencing (WES), ADOS2, and ADI-R. WES identified a homozygous, likely pathogenic variant in the MBOAT7 gene (c.855-2A>G). This is the oldest known patient with MBOAT7-related intellectual disability, whose unique features compared with previously described individuals include overgrowth with macrocephaly, metrorrhagia, ophthalmological abnormalities, basal ganglia hyperintensities, unspecified anxiety disorder, and ADHD; combined type; and hyperphagia with the absence of appendicular hypertonia and cortical atrophy. More individuals need to be identified in order to delineate the full clinical spectrum of this disorder. K E Y W O R D Sintellectual disability, MBOAT7, whole exome sequencing

A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile

“…In general, this rare disease appears to be slowly progressive, in which behavioral problems and cognitive decline worsen over adolescence. Her phenotype overlaps with many of the features already described in other reports (Jacher et al, 2019; Johansen et al, 2016; Yalnızoǧlu et al, 2019). In particular, she presents global developmental delay, motor and speech delay, motor incoordination with ataxic gate, very early‐onset age of seizures (2 months of age), and similar facial dysmorphic features.…”

“…In particular, she presents global developmental delay, motor and speech delay, motor incoordination with ataxic gate, very early‐onset age of seizures (2 months of age), and similar facial dysmorphic features. As reported by Jacher et al (2019), our patient shows macrocephaly as well and peculiar psychiatric features, characterized by hyperphagia, attention deficit hyperactivity disorder, anxiety disorder, and auto‐ and etero‐aggressive outbursts, for which she needed to be evaluated at the emergency room more than once. In addition, the dysmorphisms of the face are similar between our and Jacher's patient: curly hair, heavy eyebrows, synophrys, high nasal bridge, and full cheeks (Figure 1).…”

“…In 2016, Johansen et al (2016) reported for the first time 16 patients from six different consanguineous families harboring homozygous inactivating variants in the MBOAT7 gene (OMIM 606048). Since then, other 27 patients with MBOAT7 defects were identified (Hu et al, 2019; Jacher, Roy, Ghaziuddin, & Innis, 2019; Khan et al, 2019; Santos‐Cortez et al, 2018; Yalnızoǧlu et al, 2019). As summarized by Khan et al (2019), 13 different MBOAT7 variants in 18 families have been described until now, of which 5 are frameshift mutations, 2 are splice, 1 is nonsense, 3 are missense, 1 is a 21 bp in frame deletion, 1 is a 11,549 bp deletion.…”

“…As summarized by Khan et al (2019), 13 different MBOAT7 variants in 18 families have been described until now, of which 5 are frameshift mutations, 2 are splice, 1 is nonsense, 3 are missense, 1 is a 21 bp in frame deletion, 1 is a 11,549 bp deletion. Almost all these patients were born from consanguineous parents and share a specific clinical phenotype characterized by intellectual disability (ID), speech impairment, autistic features, early onset epilepsy, abnormal motor coordination, and similar facial features (Jacher et al, 2019; Johansen et al, 2016; Yalnızoǧlu et al, 2019).…”

Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families

“…Recently homozygous pathogenic variants within MBOAT7 have been identified in 16 families (15 consanguineous and 1 reported as non-consanguineous, although both parents were from the same village in Lebanon) as a cause of a neurodevelopmental disorder (autosomal recessive mental retardation type 57 (MIM 617188) characterized by seizures, moderate to severe ID with significant psychomotor retardation (several individuals are non-verbal and never walked, usually occurring with seizure onset), truncal hypotonia, appendicular hypertonia, features of autism spectrum disorder (ASD), below average head circumference and characteristic facial features [6–10]. The MBOAT protein family consists of five acyltransferases; lysophosphatidylinositol acyltransferase 1 (LPIAT1) encoded by the MBOAT7 gene is known to transfer arachidonic acid (AA) from arachidonoyl-CoA to lysophosphatidylinositol [11].…”