X-Autosome translocations: X-inactivation and effect on phenotype

Introduction

Chromosome translocations are common cytogenetic abnormalities that can be without apparent phenotype or can cause significant morbidity and mortality due to disruption of genes or regulatory elements or due to chromosome imbalances. Translocations involving the X-chromosome have an added layer of complexity, as in women one X-chromosome is inactivated at random, and this silencing can extend into an adjacent autosomal region, causing functional autosomal deficiencies. In cases of balanced X-autosome translocations, there is generally preferential silencing of the normal X-chromosome (Gartler and Andina, 1976), whereas in the cases of unbalanced X-autosome translocations there is preferential silencing of the abnormal X-chromosome (Mattei et al., 1982). Importantly, inactivation patterns are also influenced by the consequences of loss of the autosomal region, the presence of deletions or duplications in the derivative chromosome and the presence and location of the X-inactivation center.

Here we report a child with prenatal concern for multiple congenital anomalies, found postnatally to have multiple structural differences, akinesia and respiratory failure. Trio exome sequencing and follow-up chromosomal microarray were notable for a de novo 15q11.1q11.2 deletion on the paternal chromosome, consistent with a diagnosis of Prader Willi syndrome, and a de novo Xq22.3q28 deletion on the paternal X-chromosome, which includes multiple genes involved in neurodevelopment and metabolism. Karyotype was notable for an X:autosome translocation with Xq22qterm replaced by 15q12qterm (45,X,der(X) t(X;15)(q22;q12)), confirmed de novo by paternal karyotype. Biochemical testing was consistent with preferential inactivation of the derivative X-chromosome. Our case highlights the complexity of X-autosome translocations, reports the phenotype of a dual 15q11.1q11.2 and Xq22.3q28 deletion with a chromosome 15-X translocation, and highlights the utility of biochemical testing in elucidating the global pattern of X-inactivation.

Case report

The infant was conceived naturally to a 36-year-old G3P1→2 mother. The pregnancy was complicated by ultrasound and fetal MRI findings revealing fetal edema, cranial dysmorphisms, structural heart disease and brain malformations. Amniocentesis was declined.

The infant was born via repeat cesarean section at 37 + 2 weeks gestational age. Delivery was complicated by respiratory failure requiring positive pressure ventilation. Birth weight was 3.26 kg (75%), length was 47.6 cm (40%) and head circumference was 37.5 cm (97%). Physical examination was notable for macrocephaly, low anterior hairline, prominent metopic suture, arched eyebrows, low-set and posteriorly rotated ears, cleft palate, microretrognathia, excess nuchal skin, tapered fingers with ulnar deviation, absent labia minora and akinesia (Fig. 1). She required emergency nasal intubation by otolaryngology within 5 h of life due to respiratory failure and abnormal airway. Exome sequencing and chromosomal microarray were sent.

Fig. 1.

Patient features on examination. (a) Thick, woolly hair, prominent metopic suture, arched eyebrows, periorbital edema, low set and swollen ears and micrognathia; (b) pedal edema, small nails and bruising; (c) tapered fingers with skin bruising.

Her course was complicated by absence of spontaneous breathing, anasarca, panhypopituitarism, low alkaline phosphatase level and adrenal insufficiency. Skeletal survey showed diffusely increased bone density and bone sclerosis, consistent with underlying sclerosing bone dysplasia such as osteopetrosis or pyknodysostosis. Echocardiogram showed aortic arch hypoplasia and ventricular septal defect. Abdominal MRI showed a small left kidney, gonadal dysgenesis and uterus didelphys. Brain MRI showed a thin corpus callosum and brainstem, dysplastic cerebellum, absent olfactory bulbs, ventriculomegaly with possible cerebral aqueductal web, small adenohypophysis and restricted diffusion within the thalami and cerebellar vermis.

Chromosomal microarray and exome sequencing identified a de novo, pathogenic 6.12 Mb deletion of 15q11.1q11.2 (arr[hg19] 15q11.1q11.2 (20 071,673 – 26 194 337) × 1), including the Prader Willi/Angelman syndrome (PWS/AS) critical region, and a de novo 46.95 Mb pathogenic deletion of Xq22.3q28 (arr[hg19] Xq22.3q28 (108 281 864 – 155 236 747) × 1), including genes associated with Adrenoleukodystrophy, Hunter syndrome, Creatine Transporter Deficiency, Barth syndrome and Leigh syndrome (Table 1, Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/CD/A18). Both deletions were on the paternal alleles, clarifying the 15q11.1q11.2 deletion as PWS. Karyotype revealed 45,X,der(X)t(X;15)(q22;q12) (Fig. 2). Exome sequencing was also notable for a paternally-inherited, likely pathogenic ALPL variant (c.656T>C; p.(M219T)).

Table 1.

Genes associated with metabolic disease included in the X-chromosome deletion

Gene	Associated syndrome
ABCD1	Adrenoleukodystrophy
IDS	Hunter syndrome
NDUFA1	Leigh syndrome
SLC6A8	Creatine transporter deficiency
TAZ	Barth syndrome

Fig. 2.

Representative diagram of patient’s derivative chromosome: there is one normal chromosome 15 (yellow) and one normal X-chromosome (blue). Centromeres are denoted in black. There is one derivative chromosome, consisting of Xp through Xq22 and 15q12. The Prader Willi/Angelman syndrome critical region is not present (denoted in white)

X-inactivation studies showed greater than 99:1 skewing in blood. Additional tissues were not available for testing. Biochemical studies were not consistent with the abovementioned syndromes, suggesting preferential inactivation of the derivative X-chromosome. She passed away from respiratory failure at 4 weeks of life.

Discussion

X-autosome translocation syndromes are a diverse group of genetic syndromes caused by the sequelae of gene or regulatory region disruption, autosome silencing with X-inactivation and chromosomal imbalances. Here we describe a patient with paternal deletion of 15q11.1q11.2 and Xq22.3q28 and 15-X derivative chromosome, with X-inactivation and biochemical studies suggestive of functional monosomy 15q from skewed X-inactivation.

Pure monosomy 15q is rare and is associated with intrauterine growth restriction, coarse facies, low set and malformed ears, palatal abnormalities, micrognathia, congenital heart disease and developmental delay (Herva and Vuorinen, 1980; Mori et al., 1987; Jaillard et al., 2011; Solmaz et al., 2016). Smaller deletions within 15q are more common and are associated with low-set ears, micrognathia, increased nuchal skin, congenital heart disease, congenital diaphragmatic hernia, genitourinary malformations, ventriculomegaly, corpus callosum dysgenesis and developmental delay, overlapping with many of the features seen in our patient (Bhakta, 2005; Davidsson et al., 2008).

X-autosome translocations involving chromosome 15 have been described previously, including one child with low-set ears, ulnar deviation of the fingers, hypoplastic corpus callosum, hypotonia, developmental delay and seizures found to have a reciprocal Xp11.3; 15q26 translocation with preferential inactivation of the derivative X-chromosome and functional monosomy 15q26 (Glaser et al., 2004). Another child with t(X;15)(p21.1;q11.2), presented with feeding difficulties, horseshoe kidney, impaired swallowing, hypotonia and severe developmental delay. Parent of origin and X-inactivation studies revealed that the translocated 15q was paternal in origin and that the derivative chromosome was preferential inactivated, consistent with a diagnosis of PWS and functional monosomy 15q (Sakazume et al., 2016). The overlapping phenotype suggests that many of the congenital anomalies seen in our proband are due to functional monosomy 15q.

Our patient had severe endocrine abnormalities including pituitary and adrenal insufficiency. These abnormalities have been reported in PWS, though rarely (Heksch et al., 2017). There may be some contribution from functional monosomy of other genes on 15q or inactivation of the normal X-chromosome and functional deficiencies of genes in Xq22.3q28. Incompletely skewed X-inactivation is supported by the patient’s gonadal dysgenesis, which is associated with Xq deletions. Importantly, there is no obvious candidate gene within Xq22.3q28 to explain our patient’s endocrinopathies (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/CD/A18). Additional features in our patient that cannot be explained include her skeletal survey, consistent with osteopetrosis versus pyknodysostosis. Careful review of genes associated with osteopetrosis and pyknodysostosis was unrevealing (Table 2). Her skeletal findings were specifically reinterpreted in the context of her known ALPL gene mutation but were felt to be unrelated. Furthermore, paternal workup for hypophosphatasia was unrevealing. Interestingly, the patient’s deletion did include the IKBKG gene, in which missense variants have been reported to cause anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis and lymphedema in males (Roberts et al., 2010). Women harboring IKBKG gene deletions were not found to have a skeletal phenotype; however, investigated women did not have X-autosome translocations such as our patient (Frost et al., 2019).

Table 2.

Genes specifically evaluated on exome sequencing

Gene	Associated syndrome
ALPL	Hypophosphatasia
CA2	Osteopetrosis with renal tubular acidosis
CCDC22	Ritscher–Schinzel syndrome
CHD7	CHARGE syndrome
CLCN7	Autosomal dominant osteopetrosis type II
CTSK	Pyknodysostosis
LRP5	Autosomal dominant osteopetrosis, type I
OSTM1	Autosomal recessive osteopetrosis, type V
PLEKHM1	Autosomal recessive osteopetrosis, type VI
TCIRG1	Autosomal recessive osteopetrosis, type I
TNFRSF11A	Autosomal recessive osteopetrosis, type VII
VPS35L	Ritcher–Schinzel like syndrome
WASHC5	Ritscher–Schinzel syndrome

Our case highlights the complexity of X-autosome translocations and the role of X-inactivation studies and biochemistry in elucidating the nuances of this class of syndromes.