Clinical manifestations and genetic analysis of a newborn with Arboleda-Tham syndrome

Abstract

Arboleda-Tham syndrome (ARTHS) is a rare disorder first characterized in 2015 and is caused by mutations in lysine (K) acetyltransferase 6A (KAT6A, a.k.a. MOZ, MYST3). Its clinical symptoms have rarely been reported in newborns from birth up to the first few months after birth. In this study, a newborn was diagnosed with ARTHS based on the clinical symptoms and a mutation c.3937G>A (p.Asp1313Asn) in KAT6A. The clinical manifestations, diagnosis, and treatment of the newborn with ARTHS were recorded during follow-up observations. The main symptoms of the proband at birth were asphyxia, involuntary breathing, low muscle tone, early feeding, movement difficulties, weak crying, weakened muscle tone of the limbs, and embrace reflex, and facial features were not obvious at birth. There was obvious developmental delay, as well as hypotonic and oro-intestinal problems in the first few months after birth. Mouse growth factor was used to nourish the brain nerves, and touching, kneading the back, passive movements of the limbs, and audio-visual stimulation were used for rehabilitation. We hope that this study expands the phenotypic spectrum of this syndrome to newborns and the library of KAT6A mutations that lead to ARTHS. Consequently, the data can be used as a basis for genetic counseling and in clinical and prenatal diagnosis for ARTHS prevention.

Keywords: Arboleda−Tham syndrome; KAT6A; asphyxia; mouse growth factor; newborn.

FIGURE 1

Clinical features of the infant from birth to when 17 weeks old. The newborn at 4 weeks (A), 10 weeks (B–E), and 17 weeks (F–H). The infant shows characteristic features of Arboleda−Tham syndrome, e.g., broad nasal tip, thin upper lip, and tented mouth. A hemangioma was on the top of his head in the 10th week. Hands and feet skin color was fair and slightly cool in the 17th week.

FIGURE 2

Pedigree tree and identified of KAT6A c.3937G>A variation. (A) Family pedigree. Black symbols indicate mutation carriers, while the other symbols indicate normal carriers. The arrow indicates the family proband. The peripheral blood genomic DNA of II:2 was used for WES. The peripheral blood genomic DNA of individuals II:1, II:2, and III:2 was used for Sanger sequencing. (B) Sequencing of the heterozygous variation c.3937G>A in the KAT6A gene of family members II:1, II:2, and the proband (III:1). Genome-wide exon sequencing and variants screening 1based on the disease and/or phenotypes and also 2based on the reports in OMIM, HGMD, and ClinVar.

FIGURE 3

(A–C) Photos of the proband's mother. Physical characteristic features of this syndrome, such as bitemporal narrowing, broad nasal tip, low set ears, thin upper lip, micrognathia, and smooth philtrum are not observed.

FIGURE 4

In silico analysis. (A,B) The de novo mutation c.3937G>A located in exon 17 which is predicted to lead to a missense mutation in the glutamate/aspartate domain. (C) Evolutionary conservation of the missense mutation. Sequence alignment of amino acids reveals that the amino acid at 1313 is highly conserved across different species.