KMT2A mutations cause Wiedemann-Steiner syndrome (WDSTS), which is characterized by hypertrichosis cubiti, short stature, and distinct facial features in general. Here, we report two Chinese boys with novel nonsense KMT2A mutations. Most of their phenotypes are concordant with WDSTS. They, however, lack the key WDSTS feature-hypertrichosis cubiti. Additionally, their transverse palmar creases are absent. We further summarized the genotypes and phenotypes of the KMT2A mutation carriers. The consensus phenotypes include postnatal growth retardation, developmental delay, short stature, and intellectual disability. The common facial features include thick eyebrows, long eyelashes, downslanting, and narrow palpebral fissures, wide nasal bridge, and broad nasal tip. They have generalized hypertrichosis. A hairy back can be observed as frequently as hairy elbows in patients with KMT2A mutations. Absent palmar proximal transverse creases are only observed in these two Chinese boys. This might be due to the difference in ethnic background. Thus far, all mutations in KMT2A are located before the FYRC domain. They would truncate KMT2A mRNA transcripts. Haploinsufficiency of the histone methyltransferase activity would therefore influence transcriptional regulation. © 2016 Wiley Periodicals, Inc.

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA. Heterozygous MARS mutations have been reported to cause Charcot-Marie-Tooth disease, axonal, type 2U (CMT2U). Homozygous or compound heterozygous mutations in MARS gene would cause interstitial lung and liver disease (ILLD), a severe disease onset in infancy or early childhood. Here we report a Chinese ILLD family with two affected boys diagnosed by exome sequencing. They carry novel compound heterozygous MARS mutations (p.Asp145Asn and p.Phe802Ser). Their phenotype is concordant with ILLD description. As ILLD patients were only reported by two studies, we summarized all the reported patients and characterized the principle clinical features as interstitial lung disease, developmental delay, postnatal growth failure, non-life-threatening liver dysfunction and anemia. Genotype-phenotype correlation analysis suggests most of the ILLD mutations locate in the catalytic domain of MARS. ILLD and CMT2U might have different disease mechanism.

Haploinsufficiency of ARID1B (AT-rich interaction domain 1B) has been involved in autism spectrum disorder, nonsyndromic and syndromic intellectual disability, and corpus callosum agenesis. Growth impairment is a major clinical feature caused by ARID1B mutations; however, the mechanistic link has not been elucidated. Here, we confirm that growth delay is a common characteristic of patients with ARID1B mutations, which may be associated with dysregulation of the Wnt/β-catenin signaling pathway. An analysis of patients harboring pathogenic variants of ARID1B revealed that nearly half had short stature and nearly all had below-average height.Moreover, the percentage of patients with short stature increased with age.Knockdown of arid1b in zebrafish embryos markedly reduced body length and perturbed the expression of both chondrogenic and osteogenic genes including sox9a, col2a1a, runx2b, and col10a1. Knockout of Arid1b in chondrogenic ATDC5 cells inhibited chondrocyte proliferation and differentiation. Finally, Wnt/β-catenin signaling was perturbed in Arid1b-depleted zebrafish embryos and Arid1b knockout ATDC5 cells. These data indicate that ARID1B modulates bone growth possibly via regulation of the Wnt/β-catenin pathway, and may be an appropriate target for gene therapy in disorders of growth and development. K E Y W O R D SARID1B, bone growth, gene mutation, growth delay, short stature, Wnt/β-catenin