Table 1

Characteristics of the probands with breakpoints in genes without known/well-established association with human diseases

Proband 1Proband 2Proband 3Proband 4Proband 5
Current age12 months21 years21 years16 years8 years
Implicated genes EFNA5 SLC4A10 RET, BAHD1 PPP2R5E BLOC1S5-TXNDC5, TXNDC5
ExAC pLI* 0.8890.0030.991 (BAHD1)0.9990 (TXNDC5)
DOMINO score# 0.992 0.205 0.634 (BAHD1) 0.86 0.138 (TXNDC5)
Gene functionerythropoietin-producing human hepatocellular (EPH)-related receptor, tyrosine kinase ligandNa(+) dependent Cl-/HCO3- exchangerHeterochromatin formation, gene silencing (BAHD1)Protein phosphatase regulatory subunitEndothelial protein disulfide isomerase
Gene expression ( expressed with highest expression in: pituitary, minor salivary gland, vagina, cervix, aorta, brain.Brain (only) BAHD1 is ubiquitously expressed with highest expression in ovary, testis, thyroid, uterus, adrenal gland, fallopian tube. RET is expressed in brain, pituitary, colon and testis.Ubiquitously expressed with highest expression in tibial arteries, brain, bladder, cervix, uterus, thyroid.Ubiquitously expressed with lowest expression in brain.
Physical parameterssmall for gestational age (SGA), currently (2.4 years) weight <3rd centile; height 10th centile.NormalLow birth weight and disproportional length, currently normal.Slightly underweight at birth; currently weight and height at 3rd–10th centiles.None
ID/DDNot observedModerateSevereMildSevere
Other neurological featuresHypotoniaSpeech delay, hyperactivity, balance disorder, strange behaviour (sniffing)Developmental regression, psychiatric disturbance, abnormal EEG, unspecific MRI changesPersonality disorder, self-mutilationLack of speech, lack of ambulation, seizures
Congenital anomaliesBilateral cloudy cornea, supravalvular pulmonary stenosis, atrial septal defect, portosystemic venous shuntAstigmatismNoneRetinal dystrophy, hyperopia, astigmatismMicrocephaly, corpus callosum hypoplasia
DysmorphismSquare face, high forehead, bilateral epicanthic folds, sparse eyebrows, short and upturned nose, long and flat philtrum, narrow upper lipDistal hand camptodactyly, unilateral transverse palmar creaseLarge, soft and narrow hands with mild shortening of the metacarpals, long tapering fingersSubtle hirsutism, low neck hairline, coarse face, rounded nasal tip, very broad thumbs (maternal feature), bilateral transverse palmar creasesNone
OtherNot observedNot observedUrinary tract infection (UTI), septic ileus, Hirschsprung diseaseaCGH: dup3p22pat, history of recurrent infectionsNone
References 23–31 14 32–36 37–40 41–44 45–47
  • *pLI denotes the probability that a gene will be intolerant of loss-of-function mutations. The higher the pLI, the less tolerant the gene is of loss-of-function mutations. 

  • # DOMINO score denotes the probability of a gene to harbor dominant mutations. The higher the score is, the more probable that the gene causes a disease with dominant inheritance.

  • aCGH, array comparative genomic hybridisation; DD, developmental delay; EEG, electroencephalography; ExAC,  Exome Aggregation Consortium (; ID, intellectual delay; WES, whole-exome sequencing.