A Biallelic Variant in FRA10AC1 Is Associated With Neurodevelopmental Disorder and Growth Retardation

Case 1 (IV: 1)

The proband was the first born of a consanguineous couple and a product of uneventful pregnancy and full-term, spontaneous vaginal delivery (Figure, A). The family history was remarkable for 3 cousins with a similar disease and other 3 cousins with confirmed genetic diagnosis of mucopolysaccharidosis type IVA (Figure, A). She was small for gestational age, with low birth weight of 1.9 kg (z score = −2) and no NICU admission. According to the family, she was fine until the age of 5 months when she was admitted with chest infection, followed by 2 more admissions for the same reason at the age of 6 and 9 months. At 9 months, she was noted to have failure to thrive, central hypotonia, protruding tongue, brachycephaly, microcephaly, global developmental delay, poor vision, strabismus, and dysmorphic features.

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Figure Pedigree, Facial Images, and MRI Findings of the Patient With FRA10AC1 Variant

(A) Family pedigree showing multiple affected members in different related families. Patients IV: 1 and IV: 3 segregate the homozygous FRA10AC1 variant, which was detected by whole-exome sequencing and confirmed by Sanger sequencing. Patients III-1, III-2, and III-4 reported to have a history of ID, GDD, and brain atrophy. Patient III-4 has bilateral perisylvian syndrome, congenital post parietal disc microgyria, and seizure disorder. Patients III-9, III-10, and III-11 are genetically confirmed cases of mucopolysaccharidosis type IV (MPS IV). (B) Dysmorphic facial features of case 2 (at the age of 15 months) include deformational plagiocephaly, frontal bossing, high forehead, medial flaring of eyebrows, inverted epicanthus, strabismus, anteverted nares, pointed chin, and prominent ears with simple antihelix. Brain MRI at the age of 3.6 years: sagittal T1 WI module (C) in case 1 revealed thinning of the corpus callosum, mainly the posterior body and splenium, with diffuse brain atrophic changes with subsequent prominence of lateral ventricles and sulci, as well as the extra-axial CSF spaces. There is abnormal relatively high signal intensity in the T1 WI module along the lower aspect of the pituitary stalk likely representing ectopic posterior pituitary gland. (D) and (E) Both axial T2 WI modules show predominantly white matter paucity with atrophy of the basal ganglia and faint T2 high signal of bilateral caudate and putamina. There were bilateral subdural fluid collections larger on the right side. GDD = global developmental delay; ID = intellectual disability; rev = reverse primer.

A full workup was performed, and she was found to have a right lower pulmonary vein stenosis. At the age of 3 years, she was diagnosed with severe oropharyngeal dysphagia and subsequently started on nasogastric tube feeding. She further developed a movement disorder and spasticity.

Visual evoked potential and electroretinogram were unremarkable. A brain MRI finding at the age of 3.6 years showed a thinning of the corpus callosum, mainly the posterior body and splenium, with diffuse brain atrophic changes with consequent prominence of lateral ventricles and sulci in addition to the extra axial CSF spaces (Figures, C–E). There were bilateral subdural fluid collections larger on the right side. MRI spectroscopy at the left basal ganglia showed mildly reduced N-acetylaspartate and elevated level of choline with no lactate peak.

Tandem mass spectrometry and urine gas chromatography-mass spectrometry studies were unremarkable. Her lactate levels were initially normal; however, with every hospitalization and illness, it increased and sometimes reached as high as 6.3 mmol/L (reference: <1.4 mmol/L). Ammonia levels were unremarkable except 1 occasion where she was very sick with an ammonia level of >200 umol/L (reference: < 50 μmol/L) and along with high lactate of 6.3 mmol/L, which was possibly due to liver dysfunction and sepsis. However, total homocysteine, carbohydrate-deficient transferrin, very long-chain fatty acids, serum amino acids, urinary mucopolysaccharides, and oligosaccharides were all unremarkable. Her coagulation profile (PT/PTT and INR) tended to be high during periods of illness, where the highest was PT 32.1 seconds (reference: 11.5–14.5)/PTT 42 seconds (reference: 30–41) and INR 3 seconds (reference: 09–1.3), when she was hospitalized with septic shock and she was on inotropes and mechanical ventilation.

Chromosomal microarray revealed no clinically significant copy number variants. However, several large regions of homozygosity (3 megabases or larger) were detected, encompassing at least 10% of the genome, consistent with the degree of consanguinity. In 2016, the clinical exome sequencing (CES) including mitochondrial genome performed by a commercial laboratory showed negative results.

She died of septic and hypovolemic shock at the age of 6 years. Then, her weight was 6 kg (z score = −6.23), height 83 cm (z score = −6.47), and head circumference 45.5 cm (z score = −3.92).

Case 2 (IV: 3)

Case 2 is the younger brother of the proband (Figure, A). The pregnancy was uncomplicated, and he was born via normal spontaneous delivery at term. His newborn examination was notable for a murmur that necessitated a stay for 3 days in the nursery where he was diagnosed with a mild aortic coarctation and atrial septal defect (ASD II). After he was circumcised, he was noted to experience a mild glanular hypospadia. At 4 months of age, he developed a left inguinal hernia necessitating a surgical repair. At 6 months of age, he was noted to experience gross motor delay, and, given the positive family history, further workup was initiated including referral to neurology.

Currently, he is aged 15 months and globally delayed; he rolled over at 12 months and is still unable to sit without support. He only babbles but cannot specifically say dada or mama. He responds when called by his name; he can also follow, track, turn, and laugh when played with. He has feeding difficulties. A neurologic evaluation revealed generalized hypotonia, nystagmus, and strabismus.

On physical examination, his weight was 8.5 kg (z score = −2.36), length 84 cm (z score = +1.6), and head circumference 47.5 cm (z score = −0.08). He experienced deformational plagiocephaly, frontal bossing, high forehead, medial flaring of eyebrows, inverted epicanthus, strabismus, nystagmus, anteverted nares, pointed chin, prominent ears with simple antihelix, generalized hypotonia, mild hypospadias, one large hyperpigmented lesion in the lower back, and atopic dermatitis (Figure, B).

Metabolic screening including plasma amino acids, plasma acylcarnitines, and electrolytes were unremarkable. He has a mildly but persistently elevated PT (15.5 and 15.3).

WES, on a research basis, was performed and analyzed for him and his parents as previously described.² Consistent with the results of CES for his deceased sibling, no variants were detected in clinically relevant and established genes. However, when analyzed to search for candidate novel genes, a homozygous LOF (nonsense) variant in FRA10AC1: Chr10(GRCh38): g.93687434G>A: NM_145246.5: c.481C>T, p.(Arg161*) was identified in this patient, while parents were heterozygous. The variant was confirmed by Sanger sequencing (Figure, A). This variant was found as heterozygous in gnomAD (v2.1.1) in 10/242634 (0.004%) chromosomes and not found as homozygous in the gnomAD or a local database of 2,379 ethnically matched exomes. It introduced a premature stop codon in exon 8 and, therefore, predicted to undergo nonsense-mediated decay and results in LOF. Based on this evidence of pathogenicity and clinical correlation with the recently published cases, the CES of the deceased sister was reanalyzed, and she was confirmed to be homozygous for the same FRA10AC1 variant (Figure, A).