In this issue


A study by Kostanecka et al. (p. 3018, DOI: 10.1002/ajmg.a.35670) demonstrates the wide neurocognitive spectrum of Pallister-Killian syndrome (PKS). PKS, a sporadic disorder, stems from mosaic tetrasomy of the short arms of chromosome 12. Physical features include a high forehead, fronto-temporal alopecia, hypertelorism, hypotonia, skin pigmentation abnormalities, seizures, and psychomotor delay, among others. Case reports of children with PKS have also described a range of developmental and behavioral outcomes, but systematic studies of them do not exist, the researchers say.

The researchers studied the developmental and behavioral traits of 16 children with PKS, ages 16 months to 19 years, using questionnaires and direct interviews. Three probands between 16 and 19 months of age had severe developmental delay. Among the rest, who were older than 24 months, 11 had a developmental level equivalent to that of an eight-month-old. These youngsters were passive, didn't walk or talk, and required extensive assistance in daily living. Two higher functioning children could walk and talk, and one met criteria for autism, the researchers wrote.

Although most individuals with PKS have shown profound intellectual disability and sensory impairments, some can have mild to moderate intellectual disability, the researchers concluded, adding that formal diagnostic testing should be considered.

This article is one of six papers included in a Special Section on Pallister-Killian syndrome.


A research strategy that uncovered new chromosomal regions possibly associated with isolated congenital diaphragmatic hernia (CDH) disease suggests that non-coding variants of the genes GATA4 and NR2F2 may contribute to the development of CDH, write arrington et al. (p. 3137, DOI: 10.1002/ajmg.a.35664).

A developmental defect of the diaphragm, CDH has a high newborn mortality rate. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. But research has yet to identify the factors associated with the defect.

Researchers used the Utah Population Database to identify distantly related patients from several extended families with a high incidence of isolated CDH. using high-density genotyping, they examined shared chromosomal regions in seven patients by homozygosity exclusion rare allele mapping and phased haplotype sharing.

These patients shared three regions not previously associated with CDH, which are 2q11.2–q12.1, 4p13, and 7q11.2, and two regions previously implicated in CDH. those two regions, 8p23.1 and 15q26.2, contain GATA4 and NR2F2, genes that are involved in diaphragm formation in mice.

Three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. the researchers hope their gene mapping strategy can speed discovery of genes and regulatory elements that cause other multifactorial diseases.


The thrombopoietin gene (THPO) is a new player to consider in the wide landscape of molecular pathways involved in limb development and related pathology, researchers Graziano et al. (p. 3211, DOI: 10.1002/ajmg.a.35656) write in a research letter. Clinicians should be aware of the possibility of limb defects in families with thrombocytosis, and should determine platelet count in cases of unexplained limb reduction defects, especially familial ones, the authors add.

Hereditary thrombocytosis, usually inherited as a dominant trait, can be caused either by heterozygous mutations in THPO, which increases gene translation, or by heterozygous mutations in the THPO receptor. Limb deficiencies are a relatively common birth defect, with a reported prevalence of 0.79 in 1,000. In most cases, the etiology is not clear, and few affected infants have a positive family history. Vascular disruption is thought the most common cause, but solid data are lacking.

The letter presents a family affected by both thrombocytosis and unilateral limb defects as evidence of the association of these conditions with THPO mutations. Two such families have been described previously. Description of a third family points to the role of THPO signaling in modulating embryonic development, and in serving as a link between vascular disruptions and genetic etiology, as well as vasculogenesis and limb outgrowth. THPO has been identified as a critical factor for the proliferation of the hemangioblast, the embryonic progenitor of at least part of hematopoietic and endothelial lineages (Perlingeiro et al., 2003). THPO excess may alter vasculogenesis, conferring predisposition to vascular disruptions, Graziano et al. write.

original image

Figure 1. X-rays show limb defects in family members with thrombocytosis.