case_images: PMC10070732_01
case_images: Pedigree of the Chinese family with short stature. (A) The black circles/squares represent the affected patients diagnosed with short stature diagnosis; the white circles/squares represent the unaffected subjects. The arrow indicates the proband. The question mark indicates subject with unknown genotype but known phenotype. (B) X-ray imaging of the proband's left hand at the age of 4 years 5 months and 5 years 8 months. (C) The height growth curve of the proband during the one-year follow-up. (D) The sequencing results of the ACAN mutations. Sequence chromatograms indicate the heterozygosity for a ACAN frameshift mutation (NM_013227.3:c.7230delT; NP_001356197.1:p.Phe2410Leufs*9) in the proband and his mother. The red arrow indicates the mutation. SDS, standard deviation scores; r-hGH, Recombinant human growth hormone; y, year; m, month; BA, bone age.
case_images: fgene-14-1101695-g001.jpg
case_images: PMC10070732_01_fgene-14-1101695-g001.jpg
case_images: F1
case_images: The proband, a 4-year-old boy, came to the Xiangya Hospital Central South University with his parents due to growth retardation (Figure 1A). The BA was found to be 5 years and 6 months, as revealed by the X-ray imaging of the left hand (Figure 1B). Meanwhile, the heights of his grandmother (I-1), maternal uncle (II-1), and maternal aunt (II-4) were 145 cm ( -2.78 SDS), 153 cm ( -3.23 SDS), and 165 cm ( 0.28 SDS), respectively (Figure 1A). During this time, the height of the proband increased to 99.0 cm at 4 years 10 months (-2.17 SDS), 101.3 cm at 5 years 1 month (-1.95 SDS), 104.0 cm at 5 years and 5 months (-1.78 SDS), and 105.5 cm at 5 years and 8 months (-1.76 SDS) (Figure 1C). Meanwhile, his weight increased to 18.4 kg (-0.52 SDS) and the BA was 8 years during his latest visit, at the age of 5 years 8 months (Figure 1B). Briefly, (a) Variants within intronic, intergenic, and untranslated regions (UTRs), as well as synonymous single nucleotide variants (SNVs), were excluded from later analysis; (b) Common variants were excluded with minor allele frequency >=0.01 by the 1000 Genomes database, Genome Aggregation Database (gnomAD), version 2.1.1 and an in-house exome database of Berry Genomics; (c) Variants classified as Pathogenic/Likely Pathogenic variants, as well as variant of unknown significance (VUS) by American College of Medical Genetics (ACMG) classification, could be included; (d) Potential causative variants were then screened by a list of growth-associated genes (Supplementary Table S1); (e) Variants that were not existed in the affected family member (II-2) were excluded; (f) Bioinformatics analysis, including Polyphen-2, MutationTaster, SIFT, and CADD, were also carried out to predict the possible impacts of variants; (g) Accordingly, co-segregation analysis was conducted in the family (Supplementary Figure S1). After data filtering of (a), (b), (c), (d), and (e), only a set of 7 variants in seven genes in the proband were identified (Supplementary Figure S1, Supplementary Tables S2, S3). Phe2410Leufs*9) in exon 16 of ACAN was identified in the proband (Figure 1D).
case_images: Overview of all known ACAN mutations. (A) The red font symbolizes the mutation identified in this study. (B) The increasing SDS for each year (DeltaSDS/year) of patients with ACAN missense and small deletion mutations during GH treatment. (C) The increasing SDS for each year (DeltaSDS/year) of patients with ACAN null mutations during GH treatment. G1, globular domain 1; IGD, interglobular domain; G2, globular domain 2; KS, keratin sulfate attachment domain; CS, chondroitin sulfate attachment domain; G3, globular domain 3; SDS, standard deviation scores. **p<0.01.
case_images: fgene-14-1101695-g002.jpg
case_images: PMC10070732_01_fgene-14-1101695-g002.jpg
case_images: F2
case_images: After data filtering of (a), (b), (c), (d), and (e), only a set of 7 variants in seven genes in the proband were identified (Supplementary Figure S1, Supplementary Tables S2, S3).